Isoxazoline and isoxazole fibrogen receptor antagonists

ABSTRACT

This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex or the vitronectin receptor, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

This is a division of application Ser. No. 08/455,436, filed May 31, 1995 now U.S. Pat. No. 5,849,736.

CROSS REFERENCE TO EARLIER FILED APPLICATION

This application is a continuation-in-part of U.S. patent application Ser. No. 08/337,929, filed Nov. 10, 1994 which is a continuation-in-part of U.S. patent application Ser. No. 08/232,961, filed Apr. 22, 1994 which is a continuation-in-part of U.S. patent application Ser. No. 08/157,598, filed Nov. 24, 1993. The disclosures of these earlier filed applications are hereby incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions, including those for intranasal administration, containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.

Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.

Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.

Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A₂ synthetase inhibitors or receptor antagonists, which act against thromboxane A₂ ; and hirudin, which acts against thrombin.

Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.

GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.

In addition to GPIIb/IIIa, increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell--cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing α- and β-subunits. Integrin subfamilies contain a common β-subunit combined with different α-subunits to form adhesion receptors with unique specificity. The genes for eight distinct β-subunits have been cloned and sequenced to date.

Two members of the β1 subfamily, α4/β1 and α5/β1 have been implicated in various inflammatory processes. Antibodies to α4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti-α4 antibodies provide evidence that α4/β1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63). Anti-α4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).

The α_(v) /β₃ heterodimer, commonly referred to as the vitronectin receptor, is another member of the β₃ integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. Possible roles for α_(v) /β₃ in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571). A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the α_(v) /β₃ receptor in this process and suggest that a selective α_(v) /β₃ antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).

Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.

European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR1##

European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR2##

European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR3##

PCT Patent Application 9307867 relates to compounds having the general formula: ##STR4##

European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR5##

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

Most peptides and peptidomimetics exhibit very low oral bioavailability due to poor absorption and/or degradation in the GI tract and liver. Therefore, their use is limited to the parenteral route of administration.

Drugs with low bioavailability often have a large variability in pharmacological response due to an associated variability in drug delivery. This large variability in drug delivery may occur when the bioavailability is low because under those conditions, it takes only a small variation in bioavailability to give a large change in plasma drug concentration (W. K. Sietsema, The Absolute Oral Bioavailability of Selected Drug, International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 27 No. 4-1989 (179-211)).

Peptides and peptidomimetics have also generally shown relatively low nasal bioavailability. For example, studies with the luteinizing hormone releasing hormone (LHRH) analog, nafarelin acetate, showed that nasal bioavailability was only ˜2% (S. T. Anik, G. McRae, C. Nerenberg, A. Worden, J. Foreman, J. Hwang, S. Kushinsky, R. E. Jones, and B. Vickery; J. Pharm., Sci. 73: 684-685 (1984)). Thus, the intranasal administration of peptides and peptidomimetics is generally not recommended.

SUMMARY OF THE INVENTION

The present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes. The compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.

One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.

The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.

Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel nonpeptide compounds of Formula I (described below) which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes. The compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.

One aspect of this invention provides compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

This invention relates to novel compounds of the Formula I: ##STR6## or a pharmaceutically acceptable salt or prodrug form thereof. [1] A first embodiment of this invention provides compounds of Formula I: ##STR7## or pharmaceutically acceptable salt or prodrug forms thereof wherein: b is a single or double bond;

R¹ is selected from R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²) (CH₂)_(q) Z--, piperazinyl-(CH₂)_(q) Z-- or ##STR8## Z is selected from O, S, S(═O), or S(═O)₂ ; R² and R³ are independently selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₆ -C₁₀ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl, aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy) carbonyl;

U is selected from:

a single bond (i.e., U is not present),

--(C₁ -C₇ alkyl)-,

--(C₂ -C₇ alkenyl)-,

--(C₂ -C₇ alkynyl)-,

--(aryl)-substituted with 0-3 R^(6a), or

-(pyridyl)-substituted with 0-3 R^(6a) ;

V is selected from:

a single bond (i.e., V is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

---(C₂ -C₇ alkynyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

-(aryl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

-(pyridyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or

-(pyridazinyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

W is selected from:

a single bond (i.e., W is not present),

--(C₁ -C₇ alkyl)-,

--(C₂ -C₇ alkenyl)-,

--(C₂ -C₇ alkynyl)-, or

--(C(R⁵)₂)_(n) C(═O)N(R^(5a))--;

X is selected from:

a single bond (i.e., X is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁴, R⁸ or R¹⁴ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁴, R⁸ or R¹⁴ ;

--(C₂ -C₇ alkynyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; or ##STR9## Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkaxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; or (R²)(R³)N-(C₁ -C₁₀ alkoxy)-;

R⁴ and R^(4b) are independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ;

R⁵ is selected from H, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁ arylalkyl, adamantylmethyl or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

alternately, R⁵ and R^(5a) can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁ arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl;

R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R^(5a), SO₂ NR⁵ R^(5a), C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

R⁷ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R^(5a), SO₂ NR⁵ R^(5a), C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, or C₇ -C₁₁ arylalkyl;

R⁸ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶ ;

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-2 R⁶ ;

aryl, substituted with 0-2 R⁶ ;

5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl (C₁ -C₁₀ alkoxy) carbonyl;

R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ;

R¹⁵ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ;

C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ;

aryl, substituted with 0-5 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ;

C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ;

CO₂ R⁵ ; or

--C(═O)N(R⁵)R^(5a) ;

n is 0-4;

q is 2-7;

r is 0-3;

provided that when b is a double bond, only one of R¹⁴ or R¹⁵ is present;

provided that n, q, and r are chosen such that the number of in-chain atoms between R¹ and Y is in the range of 8-18.

[2] Preferred compounds of this first embodiment are those of Formula II (where W is a single bond (i.e., absent) and U is a single bond (i.e., absent)): ##STR10## wherein: R¹ is selected from R² HN(CH₂)_(q) O--, R² HN(R² N═)CNH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, or ##STR11## R² is selected from H, aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₁₀ alkoxycarbonyl; and/or

R⁸ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; and/or

R⁶ and R⁷ are selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo.

[3] Further preferred compounds of this first embodiment are those of Formula II (where W is a bond/absent and U is a bond/absent): ##STR12## wherein: X is selected from:

a single bond (i.e., X is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ;

--(C₂ -C₇ alkynyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; and/or

R⁸ is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated.

[4] Further preferred compounds of this first embodiment are compounds of Formula II wherein:

R¹ is ##STR13## V is phenylene or pyridylene; n is 1 or 2;

X is --(C₁ -C₂)alkyl-substituted with 0-2 R⁴

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R⁴ is --NR¹² R¹³ ;

R¹² is H, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄ alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl; and

R¹³ is H.

[5] Specifically preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:

5(R,S)-3-[[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid;

5(R,S)-N-(butanesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R,S)-N-(α-toluenesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R,S)-N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R,S)-N-(pentanoyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R,S)-3-{[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(butanesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(α-toluenesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-[(benzyloxy)carbonyl]amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(pentanoyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid.

[6] A second embodiment of this invention provides a compound of Formula I: ##STR14## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;

R¹ is selected from R^(2a) (R³)N--, R² (R³)N(R² N═)C--, R^(2a) (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, or R² (R³)N(R⁵ ON═)C--; ##STR15## Z is selected from a bond (i.e. is absent), O, S, S(═O), S(═O)₂ ;

R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R² and R³ may be hydroxy;

R^(2a) is R² or R² (R³)N(R² N═)C--;

U is selected from:

a single bond (i.e., U is not present),

--(C₁ -C₇ alkyl)-,

--(C₂ -C₇ alkenyl)-,

--(C₂ -C₇ alkynyl)-,

-(aryl)-substituted with 0-3 R^(6a), or

-(pyridyl)-substituted with 0-3 R^(6a) ;

V is selected from:

a single bond (i.e., V is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkynyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

-(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

-(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or

-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R⁶ or R⁷,

Q is selected from:

a single bond (i.e., Q is not present), --O--, --S(O)_(m) --, --N(R¹²)--, --(CH₂)_(m) --, --C(═O)--, --N(R^(5a))C(═O)--, --C(═O)N(R^(5a))--, --CH₂ O--, --OCH₂ --, --CH₂ N(R¹²)--, --N(R¹²)CH₂ --, --CH₂ C(═O)--, --C(═O)CH₂ --, --CH₂ S(O)_(m) --, or --S(O)_(m) CH₂ --,

provided that when b is a single bond, and R.sup. --U--V-- is a substituent on C5 of the central 5-membered ring of Formula I, then Q is not --O--, --S(O)_(m) --, --N(R¹²)--, --C(═O)N(R^(5a))--, --CH₂ O--, CH₂ N(R¹²)-- or --CH₂ S(O)_(m) --;

W is selected from:

--(C(R⁴)₂)_(n) C(═O)N(R^(5a))--, or

--C(═O)--N(R^(5a))--(C(R⁴)₂)_(n) --;

X is selected from:

a single bond (i.e. X is absent)

--(C(R⁴)₂)_(n) --C(R⁴)(R⁸)--C(R⁴)(R^(4a))--, with the proviso that when n is 0 or 1, then at least one of R^(4a) or R⁸ is other than H or methyl;

Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R²)(R³)N--(C₁ -C₁₀ alkoxy)-;

R⁴ is selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

alternately, two R⁴ groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond);

R^(4a) is selected from H, hydroxy, C₁ -C₁₀ alkoxy, nitro, N(R⁵)R^(5a), --N(R¹²)R¹³, --N(R¹⁶)R¹⁷, C₁ -C₁₀ alkyl substituted with 0-3 R⁶, aryl substituted with 0-3 R⁶, heteroaryl substituted with 0-3 R⁶ or C₁ -C₁₀ alkylcarbonyl;

R^(4b) is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₇ cycloalkyl, C₇ -C₁₄ bicycloalkyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³ ; halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R⁵ is selected from H, C₁ -C₈ alkyl, C₃ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₃ -C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁ arylalkyl, adamantylmethyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

alternately, R⁵ and R^(5a) when both are substituents on the same nitrogen atom (as in --NR⁵ R^(5a)) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁ arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl;

R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(m) R^(5a), SO₂ NR⁵ R^(5a), SiMe₃, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; methylenedioxy when R⁶ is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

R⁷ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(m) R^(5a), SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, or C₇ to C₁₁ arylalkyl;

R⁸ is selected from:

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶ ;

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-3 R⁶ ;

aryl, substituted with 0-3 R⁶ ;

5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl(C₂ -C₁₀ alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₇ -C₁₁ arylcarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ;

R¹⁵ is selected from:

H; R⁶ ; --CO₂ R⁵ ; --C(═O)N(R⁵)R^(5a) ;

C₁ -C₁₀ alkoxycarbonyl substituted with 0-2 R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₁ -C₁₀ alkoxy, substituted with 0-3 R⁶ ;

aryl, substituted with 0-3 R⁶ ; or

5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ;

provided that when b is a double bond, only one of R¹⁴ or R¹⁵ is present;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--C(═O)N(R^(18b))₂,

--C(═O)NHSO₂ R^(18a),

--C(═O)NHC(═O)R^(18b),

--C(═O)NHC(═O)OR^(18a),

--C(═O)NHSO₂ NHR^(18b),

--C(═S)--NH--R^(18b),

--NH--C(═O)--O--R^(18a),

--NH--C(═O)--R^(18b),

--NH--C(═O)--NH--R^(18b),

--SO₂ --O--R^(18a),

--SO₂ --R^(18a),

--SO₂ --N(18^(b))₂,

--SO₂ --NHC(═O)O18^(b),

--P(═S)(OR^(18a))₂,

--P(═O)(OR^(18a))₂,

--P(═S)(R^(18a))₂,

--P(═O)(R^(18a))₂, or ##STR16## R¹⁷ is selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₅ cycloalkylalkyl, aryl, aryl(C₁ -C₁₀ alkyl)-;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹, C₂ -C₈ alkenyl substituted with 0-2 R¹⁹, C₂ -C₈ alkynyl substituted with 0-2 R¹⁹, C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-4 R¹⁹, aryl(C₁ -C₆ alkyl)-substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹,

C₁ -C₆ alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

R^(18b) is selected from R^(18a) or H;

R¹⁹ is selected from H, halogen, CF₃, CN, NO₂, NR¹² R¹³, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁ l cycloalkylalkyl, aryl, aryl(C₁ -C₆ alkyl)-, C₁ -C₆ alkoxy, or C₁ -C₄ alkoxycarbonyl.;

m is 0-2;

n is 0-4;

q is 1-7;

r is 0-3;

provided that n, q and r are chosen such that the number of atoms connecting R¹ and Y is in the range of 8-18.

[7] Preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR17## wherein: Z is selected from a bond (i.e. is absent), O, or S; and/or

R² is selected from H, aryl(C₁ -C₁₀ alkoxy)carbonyl, or C₁ -C₁₀ alkoxycarbonyl; and/or

W is --(CH₂)_(n) C(═O)N(R^(5a))--; and/or

X is --(C(R⁴)₂)_(n) --C(R⁴)(R⁸)--CH(R⁴)--, with the proviso that when n is 0 or 1, then at least one of R^(4a) or R⁸ is other than H or methyl; and/or

R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R^(4b) ; and/or

R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, --NR⁵ R^(5a), CO₂ R⁵, S(O)_(m) R⁵, OR⁵, cyano, halo;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ; and/or

R⁷ is selected from selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo; and/or

R⁸ is selected from:

--CONR⁵ NR^(5a) ; --CO₂ R⁵ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶,

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-3 R⁶ ;

aryl, substituted with 0-2 R⁶ ;

5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ; and/or

R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂.

[8] Further preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR18## wherein: Z is selected from a bond (i.e. is absent) or O; and/or

W is --(CH₂)_(n) C(═O)N(R¹²)--; and/or

X is --C(R⁴)(R⁸)--C(R⁴)₂ --.

[9] Further preferred compounds of this second embodiment are compounds of Formula Ia, wherein:

R¹ is R² NHC(═NR²)--, R² NHC(═NR²)NH-- and V is phenylene or pyridylene, or

R¹ is ##STR19## and V is a single bond (i.e. V is absent); n is 1 or 2;

X is --CHR⁸ CH₂ --;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R⁶ is selected from H, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, --NR⁵ R^(5a), CO₂ R⁵, S(O)_(m) R⁵, OR⁵, cyano, halo;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substituent on aryl; or

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl;

R⁸ is selected from:

--CONR⁵ NR^(5a) ; --CO₂ R⁵ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶,

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ; aryl, substituted with 0-2 R⁶ ;

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R⁶ ;

R¹² is selected from H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and

R¹³ is H.

[10], [35] Specifically preferred compounds of this second embodiment are compounds, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt or prodrug forms thereof, selected from:

3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoic acid;

3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-pentanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoic acid;

3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoic acid;

3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoic acid;

3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonamido)butanoic acid;

3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(adamantylmethylaminocarbonyl)propanoic acid;

3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(1-azabicyclo[3.2.2]nonylcarbonyl)propanoic acid;

3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(phenethylaminocarbonyl)propanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(3-pyridylethyl)propanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(2-pyridylethyl)propanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(phenylpropyl)propanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(phenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-methyl-phenyl-sulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(butanesulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(propanesulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(ethanesulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(methyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(ethyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(1-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(1-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(benzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-methylbenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-methoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-chlorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-bromobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-fluorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-phenoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-(methyloxyethyl)-oxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-pyridinylcarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-pyridinylcarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-pyridinyl-carbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-(2-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-(3-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-(4-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-butyloxyphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-thienylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-iodophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-2-methoxycarbonylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2,4,6-trimethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-methoxyphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2,3,5,6-tetramethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2-(4-cyanophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-propylphenylsulfonyl)-2,3-diaiminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-phenylethylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-isopropylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-phenylpropylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-pyridylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(phenylaminosulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(benzylaminosulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(dimethylaminosulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(phenylaminocarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-fluorophenylaminocarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(1-naphthylaminocarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(benzylaminocarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-bromo-2-thienylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methyl-2-benzothienylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-cyclopropylethoxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N³ -[2-{5-(4-formamidinophenyl)-isoxazolin-3-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(2-methyl-phenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(3-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N² -(4-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

said enantiomeric and diasteriomeric forms being selected from:

(R,S), (R,S);

(R), (R,S);

(S), (R, S);

(R), (R);

(S), (R);

(R), (S);

(S), (S).

The prodrug forms of the compounds of the second embodiment include the following esters:

methyl;

ethyl;

isopropyl;

methylcarbonyloxymethyl-;

ethylcarbonyloxymethyl-;

t-butylcarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

1-(methylcarbonyloxy)ethyl-;

1-(ethylcarbonyloxy)ethyl-;

1-(t-butylcarbonyloxy)ethyl-;

1-(cyclohexylcarbonyloxy)ethyl-;

i-propyloxycarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

t-butyloxycarbonyloxymethyl-;

1-(i-propyloxycarbonyloxy)ethyl-;

1-(cyclohexyloxycarbonyloxy)ethyl-;

1-(t-butyloxycarbonyloxy)ethyl-;

dimethylaminoethyl-;

diethylaminoethyl-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.

[11] Also preferred compounds of the second embodiment are those compounds of Formula Ic: ##STR20## wherein: b is a single or double bond;

R¹ is selected from R^(2a) (R³)N--, R² (R³)N(R² N═)C--, R^(2a) (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, or R² (R³)N(R⁵ ON═)C--; ##STR21## Z is selected from a bond (i.e. is absent), O, or S; R² and R³ are independently selected from: H; C₁ -C₆ alkyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

R^(2a) is R² or R² (R³)N(R² N═)C;

U is a single bond (i.e., U is not present),

V is selected from:

a single bond (i.e., V is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkynyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

--(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or

-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R⁶ or R⁷,

Q is selected from

a single bond (i.e., Q is not present), --O--, --S(O)_(m) --, --N(R¹²)--, --(CH₂)_(m) --, --C(═O)--, --N(R^(5a))C(═O)--, --C(═O)N(R^(5a))--, --CH₂ O--, --OCH₂ --, --CH₂ N(R¹²)--, --N(R¹²)CH₂ --, --CH₂ C(═O)--, --C(═O)CH₂ --, --CH₂ S(O)_(m) --, or --S(O)_(m) CH₂ --,

provided that when b is a single bond, and R¹ --U--V-- is a substituent on C₅ of the central 5-membered ring in Formula I, then Q is not --O--, --S(O)_(m) --, --N(R¹²)--, --C(═O)N(R^(5a))--, --CH₂ O--, CH₂ N(R¹²)-- or --CH₂ S(O)_(m) --;

W is selected from:

--(C(R⁴)₂)--C(═O)--N(R^(5a))--, or --C(═O)--N(R^(5a))--(C(R⁴)₂)--;

X is --C(R⁴)₂ --CHR^(4a) --;

R⁴ is selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

R^(4a) is selected from hydroxy, C₁ -C₁₀ alkoxy, nitro, --N(R⁵)R^(5a), --N(R¹²)R¹³, or --N(R¹⁶)R¹⁷, C₁ -C₁₀ alkyl substituted with 0-3 R⁶, aryl substituted with 0-3 R⁶, heteroaryl substituted with 0-3 R⁶, or C₁ -C₁₀ alkylcarbonyl;

R^(4b) is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³, halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridyl;

R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R^(4b) ;

R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁ arylalkyl, or adamantylmethyl, C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

alternately, R⁵ and R^(5a) can be taken together to be 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl or C₇ -C₁₁ arylalkoxycarbonyl;

R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b)

Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo;

R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹⁵ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--C(═O)N(R^(18b))₂,

--SO₂ --R^(18a), or

--SO₂ --N(R^(18b))₂ ;

R¹⁷ is selected from: H or C₁ -C₄ alkyl;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₆ alkyl)-substituted with 0-4 R¹⁹,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,.benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

R^(18b) is selected from R^(18a) or H;

R¹⁹ is selected from H, halogen, CF₃, CN, NO₂, NR¹² R¹³, C₁ -C₈ alkyl; C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ alkoxy, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, aryl, heteroaryl, aryl(C₁ -C₆ alkyl)-, or C₁ -C₄ alkoxycarbonyl;

n is 0-4;

q is 1-7;

r is 0-3;

provided that n, q, and r are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.

[12] Further preferred compounds of the second embodiment of Formula Ic are those compounds of Formula Ib: ##STR22## wherein: R¹ is selected from: R² (R³)N--, R² NH(R² N═)C--, R² NH(R² N═)CNH--, R² R³ N(CH₂)_(p') Z--, R² NH(R² N═)CNH(CH₂)_(p") Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, or R² (R³)N(R⁵ ON═)C--; ##STR23## n is 0-1; p' is 4-6;

p" is 2-4;

Z is selected from a bond (i.e. is absent) or O;

V is a single bond (i.e., V is not present), -(phenyl)- or -(pyridyl)-;

W is selected from:

--(C(R⁴)₂)--C(═O)--N(R^(5a))--,

--C(═O)--N(R^(5a))--CH₂ --;

X is selected from:

--CH₂ --CHN(R¹⁶)R¹⁷ --, or

--CH₂ --CHNR⁵ R^(5a) --;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--S(═O)₂ --R^(18a) or

--SO₂ --N(R^(18b))₂ ;

R¹⁷ is selected from H or C₁ -C₅ alkyl;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₆ alkyl)-substituted with 0-4 R¹⁹,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹.

[13] Further preferred compounds of Formula Ib are those compounds wherein:

R¹ is R² NH(R² N═)C-- or R² HN(R² N═)CNH-- and V is phenylene or pyridylene; or

R¹ is ##STR24## and V is a single bond (i.e. V is absent); n is 1 or 2;

R^(18a) is selected from:

C₁ -C₄ alkyl substituted with 0-2 R¹⁹,

C₂ -C₄ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₄ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₇ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₄ alkyl)-substituted with 0-4 R¹⁹,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

C₁ -C₄ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R¹⁹.

[14] Specifically preferred compounds of Formula Ib are compounds, or pharmaceutically acceptable salt forms thereof, selected from:

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methyl-phenyl-sulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(butanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(propanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(ethanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(ethyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-chlorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-bromobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-phenoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(methyloxyethyl)-oxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-pyridinyl-carbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(2-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(3-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(4-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-butyloxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-iodophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-2-methoxycarbonylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methoxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2,3,5,6-tetramethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-cyanophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-propylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-phenylethylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-isopropylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-phenylpropylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(dimethylaminosulfonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorophenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-naphthylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-bromo-2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methyl-2-benzothienylsulfonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid,

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid, and

N³ -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid.

N³ -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.

N³ -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.

N³ -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid.

N³ -[2-{5-(4-formamidinophenyl)-isoxazolin-3(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

[15] Also specifically preferred are prodrug esters of the specifically preferred compounds of Formula Ib, said esters being chosen from the group consisting of:

methyl;

ethyl;

isopropyl;

methylcarbonyloxymethyl-;

ethylcarbonyloxymethyl-;

t-butylcarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

1-(methylcarbonyloxy)ethyl-;

1-(ethylcarbonyloxy)ethyl-;

1-(t-butylcarbonyloxy)ethyl-;

1-(cyclohexylcarbonyloxy)ethyl-;

i-propyloxycarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

t-butyloxycarbonyloxymethyl-;

1-(i-propyloxycarbonyloxy)ethyl-;

1-cyclohexyloxycarbonyloxy)ethyl-;

1-(t-butyloxycarbonyloxy)ethyl-;

dimethylaminoethyl-;

diethylaminoethyl-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.

[16] A third embodiment of this invention provides a compound of Formula Id: ##STR25## or a pharmaceutically acceptable salt or prodrug form thereof wherein: R¹ is selected from is selected from R² (R³)N--, R² (R³)N(R² N═)C--, R² (R³)N(R² N═)CN(R²)--, R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)(CH₂)_(q) Z--, piperazinyl-(CH₂)_(q) Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--, ##STR26## Z is selected from a bond (i.e., is absent), O, S, S(═O), or S(═O)₂ ;

R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; , C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R² and R³ may be hydroxy;

U is selected from:

a single bond (i.e., U is absent)

C₁ -C₇ alkylene,

C₂ -C₇ alkenylene,

C₂ -C₇ alkynylene,

arylene substituted with 0-3 R^(6a),, or

pyridylene substituted with 0-3 R^(6a) ;

V is selected from:

a single bond (i.e., V is absent);

C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ;

phenylene substituted with 0-4 R⁶ or R⁷ ;

pyridylene substituted with 0-3 R⁶ or R⁷ ;

pyridazinylene substituted with 0-3 R⁶ or R⁷ ;

X is selected from:

a single bond (i.e., X is absent);

--(CH₂)_(n) C(═O)N(R¹²)--;

C₁ -C₇ alkylene substituted with 0-6 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ;

Y is selected from:

hydroxy,

C₁ to C₁₀ alkyloxy,

C₃ to C₁₁ cycloalkyloxy,

C₆ to C₁₀ aryloxy,

C₇ to C₁₁ aralkyloxy,

C₃ to C₁₀ alkylcarbonyloxyalkyloxy,

C₃ to C₁₀ alkoxycarbonyloxyalkyloxy,

C₂ to C₁₀ alkoxycarbonylalkyloxy,

C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy,

C₅ to C₁₀ cycloalkoxycarbonylalkyloxy,

C₇ to C₁₁ aryloxycarbonylalkyloxy,

C₈ to C₁₂ aryloxycarbonyloxyalkyloxy,

C₈ to C₁₂ arylcarbonyloxyalkyloxy,

C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

(R²)(R³)N--(C₁ -C₁₀ alkoxy)-;

R¹⁴ and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR27## D, E, F and G are each independently selected from: C(R^(6a))₂ ;

carbonyl;

a heteroatom moiety selected from N, N(R¹²), O, provided that no more than 2 of D, E, F and G are N, N(R¹²), O, S, or C(═O);

alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;

R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ;

R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R^(5a), C(═O)R^(5a), CONHR^(5a), CON(R¹²)₂, OC(═O)R^(5a), OC(═O)OR^(5a), OR^(5a), OC(═O)N(R¹²)₂, OCH₂ CO₂ R^(5a), CO₂ CH₂ CO₂ R^(5a), N(R¹²)₂, NO₂, NR¹² C(═O)R^(5a), NR¹² C(═O)OR^(5a), NR¹² C(═O)N(R¹²)₂, NR¹² SO₂ N(R¹²)₂, NR¹² SO₂ R^(5a), S(O)_(p) R^(5a), SO₂ N(R¹²)₂, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substituent on aryl;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

R⁸ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-6 R⁶ ;

C₃ -C₈ cycloalkyl, substituted with 0-6 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-5 R⁶ ;

aryl, substituted with 0-5 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryls or heteroaryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R⁵ and R^(5a) are selected independently from H, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-8 R⁴ ;

R¹⁵ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ;

C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ;

aryl, substituted with 0-5 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ;

C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ;

CO₂ R⁵ ; or

--C(═O)N(R¹²)R¹³ ;

n is 0-4;

p is 1-3;

q is 1-7;

r is 0-3;

provided that n, p, q and r are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.

[47] Also preferred compounds of the second embodiment are those compounds of Formulae Ie or If: ##STR28## or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, wherein:

R¹ is R² (R³)N(R² N═)C--, R² (R³)N(R² N═)CN(R²)--, or R² (R³)N--;

R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R² and R³ may be hydroxy;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl(C₂ -C₁₀ alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₇ -C₁₁ arylcarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--C(═O)N(R^(18b))₂,

--C(═O)NHSO₂ R^(18a),

--C(═O)NHC(═O)R^(18b),

--C(═O)NHC(═O)OR^(18a),

--C(═O)NHSO₂ NHR^(18b),

--C(═S)--NH--R^(18b),

--NH--C(═O)--O--R^(18a),

--NH--C(═O)--R^(18b),

--NH--C(═O)--NH--R^(18b),

--SO₂ --O--R^(18a),

--SO₂ --R^(18a),

--SO₂ --N(18^(b))₂,

--SO₂ --NHC(═O)O18^(b),

--P(═S)(OR^(18a))₂,

--P(═O)(OR^(18a))₂,

--P(═S)(R^(18a))₂,

--P(═O)(R^(18a))₂, or ##STR29## R^(18a) is selected from: C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₆ alkyl)-substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹,

C₁ -C₆ alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

R^(18b) is selected from R^(18a) or H;

R¹⁹ is selected from H, halogen, CF₃, CN, NO₂, NR¹² R¹³, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, aryl, aryl(C₁ -C₆ alkyl)-, C₁ -C₆ alkoxy, or C₁ -C₄ alkoxycarbonyl;

Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₁ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R²)(R³)N--(C₁ -C₁₀ alkoxy)-;

m is 0-2;

n is 0-2; and

p is 1-5.

[17] Preferred compounds of this third embodiment are compounds of Formula III: ##STR30## wherein: R¹ is selected from R² HN--, H₂ N(R² N═)C--, H₂ N(R² N═)CNH--, R² HN(CH₂)_(q) O--, H₂ N(R² N═)CNH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--, ##STR31## R² and R³ are selected from H; C₁ -C₆ alkyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or C₁ -C₁₀ alkoxycarbonyl;

R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ;

V is selected from:

a single bond (i.e., V is absent);

C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ;

phenylene substituted with 0-3 R⁶ or R⁷ ;

pyridylene substituted with 0-3 R⁶ or R⁷ ;

pyridazinylene substituted with 0-3 R⁶ or R⁷ ;

X is selected from --(CH₂)_(n) C(═O)N(R¹²)--, C₁ -C₇ alkylene substituted with 0-1 R⁴, C₂ -C₇ alkenylene, or C₂ -C₇ alkynylene;

Y is selected from:

hydroxy,

C₁ to C₁₀ alkyloxy,

C₃ to C₁₁ cycloalkyloxy,

C₆ to C₁₀ aryloxy,

C₇ to C₁₁ aralkyloxy,

C₃ to C₁₀ alkylcarbonyloxyalkyloxy,

C₃ to C₁₀ alkoxycarbonyloxyalkyloxy,

C₂ to C₁₀ alkoxycarbonylalkyloxy,

C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy,

C₅ to C₁₀ cycloalkoxycarbonylalkyloxy,

C₇ to C₁₁ aryloxycarbonylalkyloxy,

C₈ to C₁₂ aryloxycarbonyloxyalkyloxy,

C₈ to C₁₂ arylcarbonyloxyalkyloxy,

C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or

C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

Z is selected from O or CH₂ ;

D, E, F and G are each independently selected from:

CH₂ ;

carbonyl;

a heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S;

alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;

R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo;

R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl;

n is 0-4;

p is 1-3;

q is 1-7;

r is 0-3;

provided that n, p, q and r are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.

[18] Further preferred compounds of this third embodiment are compounds of Formula II wherein:

R¹ is R² NHC(═NR²)-- and V is phenyl or pyridyl or

R¹ is ##STR32## and V is a single bond (i.e. V is absent); n is 1 or 2;

X is C₁ -C₄ alkylene substituted with 0-1 R⁴ ;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R¹² and R¹³ are each independently selected from H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and

R¹³ is H.

[19] Specifically preferred compounds of this third embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)- 1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5,7-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;

5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;

5(R,S)-3-(4-amidinophenyl)-8-[2-(benzyloxycarbonylamino)-2-carboxyethyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene.

[20] A fourth embodiment of this invention provides compounds of Formula I: ##STR33## or pharmaceutically acceptable salt or prodrug forms thereof, wherein: R¹ is selected from:

R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)(CH₂)_(q) Z--, piperazinyl-(CH₂)_(q) Z-- or ##STR34## Z is selected from O, S, S(═O), S(═O)₂ ; R² and R³ are independently selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₄ -C₁₁ cycloalkylcarbonyloxy (C₁ -C₄ alkoxy)carbonyl;

U is optionally present and is selected from C₁ -C₇ alkylene, C₂ -C₇ alkenylene, C₂ -C₇ alkynylene, arylene, or pyridylene;

V is selected from:

a single bond (i.e., V is absent);

C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ;

phenylene substituted with 0-4 R⁶ or R⁷ ;

pyridylene substituted with 0-3 R⁶ or R⁷ ;

pyridazinylene substituted with 0-3 R⁶ or R⁷ ;

W is -(aryl)-Z¹ -, wherein said aryl is substituted with 0-6 R⁶ or R⁷ ;

Z¹ is selected from a single bond (i.e., Z¹ is absent), --CH₂ --, O or S;

X is selected from:

a single bond (i.e., X is absent);

C₁ -C₇ alkylene substituted with 0-6 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ;

Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R²)(R³)N--(C₁ -C₁₀ alkoxy)-;

R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ;

R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R^(5a), C(═O)R^(5a), CONHR^(5a), CON(R¹²)₂, OC(═O)R^(5a), OC(═O)OR^(5a), OR^(5a), OC(═O)N(R¹²)₂, OCH₂ CO₂ R^(5a), CO₂ CH₂ CO₂ R^(5a), N(R¹²)₂, NO₂, NR¹² C (═O) R^(5a), NR¹² C(═O)OR^(5a), NR¹² C(═O)N(R¹²)₂, NR¹² SO₂ N(R¹²)₂, NR¹² SO₂ R^(5a), S(O)_(p) R^(5a), SO₂ N(R¹²)₂, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;

C₆ to C₁₀ aryl optionally substituted with halogen, alkoxy, alkyl, --CF₃, S(O)_(m) Me, or --NMe₂ ; or

C₇ to C₁₁ arylalkyl said aryl being optionally substituted with halogen, alkoxy, alkyl, --CF₃, S(O)_(m) Me, or --NMe₂ ;

R⁸ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-6 R⁶ ;

C₃ -C₈ cycloalkyl, substituted with 0-6 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-5 R⁶ ;

aryl, substituted with 0-5 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl(C₁ -C₁₀ alkoxy)carbonyl;

R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R¹²)R¹³ ;

R⁵ and R^(5a) are selected independently from H, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-8 R⁴ ;

R¹⁵ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 6-8 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ;

C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ;

aryl, substituted with 0-5 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ;

C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ;

CO₂ R⁵ ; or

--C(═O)N(R¹²)R¹³ ;

n is 0-4;

q is 2-7;

r is 0-3;

provided that n, q, and r are chosen such that the number of atoms between R¹ and Y is about 8-17.

[21] Preferred compounds of this fourth embodiment are those of Formula IV: ##STR35## wherein: R¹ is selected from R² HN(CH₂)_(q) O--, R² HN(R² N═C)NH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, or ##STR36## Z is O; R² is selected from H, aryl(C₁ -C₁₀)alkoxycarbonyl, C₁ -C₁₀ alkoxycarbonyl;

V is selected from:

a single bond (i.e., V is absent);

C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ;

C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ;

C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ;

phenylene substituted with 0-3 R⁶ or R⁷ ;

pyridylene substituted with 0-3 R⁶ or R⁷ ;

pyridazinylene substituted with 0-3 R⁶ or R⁷ ;

Z¹ is selected from a single bond (i.e., Z¹ is absent), O or S;

X is selected from:

a single bond (i.e., X is absent);

C₁ -C₇ alkylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkenylene substituted with 0-3 R⁴, R⁸ or R¹⁵ ;

C₂ -C₇ alkynylene substituted with 0-3 R⁴, R⁸ or R¹⁵ ;

Y selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ;

R⁶ and R⁷ are selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo;

R⁸ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated;

R¹² and R¹³ are independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;

R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R¹²)R¹³ ;

R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R⁴ ;

n is 0-4;

q is 2-7;

provided that n and q are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.

[22] Further preferred compounds of this fourth embodiment are compounds of Formula IV wherein:

R¹ is R² HN(CH₂)_(q) O-- or ##STR37## V is C₁ -C₃ alkylene; Z¹ is a single bond (i.e. Z¹ is absent) or O;

X is C₁ -C₃ alkylene substituted with 0-1 R⁴ ;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R¹² and R¹³ are independently selected from H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₆ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;

R¹³ is H.

[23] Specifically preferred compounds of this fourth embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:

5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]hydrocinnamic acid;

5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]hydrocinnamic acid;

5(R,S) -4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]hydrocinnamic acid;

5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]phenoxyacetic acid;

5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]phenoxyacetic acid;

5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]phenoxyacetic acid.

[24] A fifth embodiment of this invention provides a compound of Formula I: ##STR38## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;

R¹ is selected from R^(2a) (R³)N--, R² (R³)N(R² N═)C--, R^(2a) (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--; ##STR39## Z is selected from a bond (i.e. is absent), O, S, S(═O), S(═O)₂ ;

R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R² and R³ may be hydroxy;

R^(2a) is R² or R² (R³)N(R² N═)C;

U is selected from:

a single bond (i.e., U is not present),

--(C₁ -C₇ alkyl)-,

--(C₂ -C₇ alkenyl)-,

--(C₂ -C₇ alkynyl)-,

-(aryl)-substituted with 0-3 R^(6a), or

-(pyridyl)-substituted with 0-3 R^(6a) ;

V is selected from:

a single bond (i.e., V is not present);

--(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

--(C₂ -C₇ alkynyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ;

-(phenyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

-(pyridyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or

-(pyridazinyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ;

W is selected from: ##STR40## X is selected from: a single bond (i.e. X is absent) --(C(R⁴)₂)_(n) --C(R⁴)(R⁸)--C(R⁴)(R^(4a))--, with the proviso that when n is 0 or 1, then at least one of R^(4a) or R⁸ is other than H or methyl;

Y is selected from:

hydroxy,

C₁ to C₁₀ alkyloxy,

C₃ to C₁₁ cycloalkyloxy,

C₆ to C₁₀ aryloxy,

C₇ to C₁₁ aralkyloxy,

C₃ to C₁₀ alkylcarbonyloxyalkyloxy,

C₃ to C₁₀ alkoxycarbonyloxyalkyloxy,

C₂ to C₁₀ alkoxycarbonylalkyloxy,

C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy.

C₅ to C₁₀ cycloalkoxycarbonylalkyloxy,

C₇ to C₁₁ aryloxycarbonylalkyloxy,

C₇ to C₁₂ aryloxycarbonyloxyalkyloxy,

C₈ to C₁₂ arylcarbonyloxyalkyloxy,

C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(R²)(R³)N--(C₁ -C₁₀ alkoxy)-;

Z¹ is --C--, --O--, or --NR²² --;

Z² is --O--, or --NR²² --;

R⁴ is selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkylcarbonyl, aryl, arylalkylene cycloalkyl, or cycloalkylalkylene;

alternately, two R⁴ groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond);

R^(4a) is selected from H, hydroxy, C₁ -C₁₀ alkoxy, nitro, N(R⁵)R^(5a), --N(R¹²)R¹³, --N(R¹⁶)R¹⁷, C₁ -C₁₀ alkyl substituted with 0-3 R⁶, aryl substituted with 0-3 R⁶, or C₁ -C₁₀ alkylcarbonyl;

R^(4b) is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³ ; halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, or pyridyl;

R⁵ is selected from H, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

alternately, R⁵ and R^(5a) when both are substituents on the same nitrogen atom (as in --NR⁵ R^(5a)) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁ arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl;

R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ;

R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR⁵, OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R⁵, SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substiuent on aryl; or

a 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

R⁷ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(m) R^(5a), SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, or C₇ to C₁₁ arylalkyl;

R⁸ is selected from:

R⁶ ;

C₂ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶ ;

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ;

C₅ -C₆ cycloalkenyl, substituted with 0-3 R⁶ ;

aryl, substituted with 0-3 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ;

R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₇ -C₁₁ arylcarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ;

R¹⁵ is selected from:

H;

R⁶ ;

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ;

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ;

C₁ -C₁₀ alkoxy, substituted with 0-3 R⁶ ;

aryl, substituted with 0-3 R⁶ ;

5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ;

C₁ -C₁₀ alkoxycarbonyl substituted with 0-2 R⁶ ;

-CO₂ R⁵ ; or

--C(═O)N(R¹²)R¹³ ;

provided that when b is a double bond, only one of R¹⁴ or R¹⁵ is present;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--C(═O)N(R^(18b))₂,

--C(═O)NHSO₂ R^(18a),

--C(═O)NHC(═O)R^(18b),

--C(═O)NHC(═O)OR^(18a),

--C(═O)NHSO₂ NHR^(18b),

--C(═S)--NH--R^(18b),

--NH--C(═O)--O--R^(18a),

--NH--C(═O)--R^(18b),

--NH--C(═O)--NH--R^(18b),

--SO₂ --O--R^(18a),

--SO₂ --R^(18a),

--SO₂ --N(18^(b))₂,

--SO₂ --NHC(═O)O18^(b),

--P(═S)(OR^(18a))₂,

--P(═O)(OR^(18a))₂,

--P(═S)(R^(18a))₂,

--P(═O)(R^(18a))₂, or ##STR41## R¹⁷ is selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₅ cycloalkylalkyl, aryl, aryl(C₁ -C₁₀ alkyl)-;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₆ alkyl)-substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹,

C₁ -C₆ alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹ ;

R^(18b) is selected from R^(18a) or H;

R¹⁹ is selected from H, halogen, CF₃, CN, NO₂, NR¹² R¹³, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, aryl, aryl(C₁ -C₆ alkyl)-, C₁ -C₆ alkoxy, or C₁ -C₄ alkoxycarbonyl;

R²⁰ and R²¹ are each independently selected from H, C₁ -C₁₀ alkyl, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), NR⁵ C(═O)R^(5a), NR¹² R¹³, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, or C₇ -C₁₁ arylalkyl;

R²² is selected from C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₅ cycloalkylalkyl, aryl, aryl (C₁ -C₁₀ alkyl)-; C(═O)R^(5a), CO₂ R^(5b), --C(═O)N(R⁵)R^(5a), or a bond to X;

m is 0-2;

n is 0-2;

p is 1-2;

q is 1-7;

r is 0-3;

provided that n, q and r are chosen such that the number of atoms connecting R¹ and Y is in the range of 8-17.

[25] Preferred compounds of this embodiment are those compounds of Formula Ic: ##STR42## wherein: Z is selected from a bond (i.e. is absent), O, or S;

R² and R³ are independently selected from: H; C₁ -C₆ alkyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

U is a single bond (i.e., U is not present);

X is --CHR^(4a) --;

R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R^(4b) ;

R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo;

R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹⁵ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--S(═O)₂ --R^(18a) ;

R¹⁷ is selected from: H or C₁ -C₄ alkyl;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-2 R¹⁹,

aryl(C₁ -C₆ alkyl)-substituted with 0-2 R¹⁹,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹ ;

C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹.

[26] Further preferred compounds of this embodiment are compounds of Formula Ib: ##STR43## wherein: R¹ is selected from: R² (R³)N--, R² NH(R² N═)C--, R² R³ N(CH₂)_(p") Z--, R² NH(R² N═)CNH(CH₂)_(p') Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--; ##STR44## n is 0-1; p' is 2-4;

p" is 4-6;

Z is selected from a bond (i.e. is absent) or O;

R³ is H or C₁ -C₅ alkyl;

V is a single bond (i.e., V is not present), or -(phenyl)-;

X is selected from:

--CH₂ --,

--CHN(R¹⁶)R¹⁷ --, or

CHNR⁵ R^(5a) --;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R^(18a) is selected from:

C₁ -C₄ alkyl substituted with 0-2 R¹⁹,

C₂ -C₄ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₄ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₄ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-2 R¹⁹,

aryl(C₁ -C₄ alkyl)-substituted with 0-2 R¹⁹,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹ ;

C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹.

[27] Further preferred compounds of this fifth embodiment are compounds of Formula Ib wherein:

R¹ is R² NH(R² N═)C-- or R² NH(R² N═)CNH-- and V is phenyl or pyridyl; or

R¹ is ##STR45## and V is a single bond (i.e. V is absent) n is 1-2;

X is selected from:

--CH₂ --,

--CHN(R¹⁶)R¹⁷ --, or

--CHNR⁵ R^(5a) --;

W is selected from: ##STR46## m is 1-3; Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R¹⁹ is H, halogen, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, cyclopropylmethyl, aryl, or benzyl;

R²⁰ and R²¹ are both H;

R²² is H, C₁ -C₄ alkyl or benzyl.

[28] Specifically preferred compounds of this fifth embodiment are compounds of Formula Ib, or pharmaceutically acceptable salt forms thereof, selected from:

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine;

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azepine;

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine;

3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperazine-2-one;

6-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine-2-one;

5-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine-2-one;

7-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azetidine-2-one;

2-(R,S) -carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrazolidine;

3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]morpholine.

In the present invention it has been discovered that the compounds of Formula I above are useful as inhibitors of cell-matrix and cell--cell adhesion processes. The present invention includes novel compounds of Formula I and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formula I.

In the present invention it has also been discovered that the compounds of Formula I above are useful as inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa). The compounds of the present invention inhibit the activation and aggregation of platelets induced by all known endogenous platelet agonists.

The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

The compounds of Formula I of the present invention are useful for the treatment (including prevention) of thromboembolic disorders. The term "thromboembolic disorders" as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.

The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, infammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, tumors, metastasis, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula I of the present invention may also be useful for wound healing.

The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.

Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.

The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.

Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.

The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.

The compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.

By "therapeutically effective amount" it is meant an amount of a compound of Formula I that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin™) and heparin.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane™. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin and other inhibitors of thrombin synthesis such as Factor XA. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.

The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase™. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The compounds or combination products of the present invention may also be useful for the treatment, including prevention, of metastatic cancer.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.

The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

When any variable (for example but not limited to, R², R⁴, R⁶, R⁷, R⁸, R¹², and R¹⁴, n, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁴, then said group may optionally be substituted with up to two R⁴ and R⁴ at each occurrence is selected independently from the defined list of possible R⁴. Also, by way of example, for the group --N(R^(5a))₂, each of the two R^(5a) substituents on N is independently selected from the defined list of possible R^(5a). Similarly, by way of example, for the group --C(R⁷)₂ --, each of the two R⁷ substituents on C is independently selected from the defined list of possible R⁷.

When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.

When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "C₁ -C₁₀ " denotes alkyl having 1 to 10 carbon atoms); "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1)); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

The terms "alkylene", "alkenylene", "phenylene", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such "alkylene", "alkenylene", "phenylene", and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", "-(alkenyl)-" and "-(phenyl)-", and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl optionally substituted with 0-3 groups independently selected from methyl, methoxy, amino, hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; the term "arylalkyl" represents an aryl group attached through an alkyl bridge.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term "heteroaryl" refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.

As used herein, the term "chiral amine" refers to any amine containing compound that also contains a chiral center. Such compounds include, by way of example and without limitation, either enantiomer of cinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. Examples of representative carboxyl and amino prodrugs are included under the definition of R², R³, and Y.

The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.

As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.; 1985; p. 1418, the disclosure of which is hereby incorporated by reference.

The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The following abbreviations are used herein:

    ______________________________________                                         Alata.       3-aminopropionic acid                                             Boc          tert-butyloxycarbonyl                                             Boc.sub.2 O  di-tert-butyl dicarbonate                                         BOP          benzotriazolyl-N-oxytris(dimethylamino)-                                       phosphonium hexafluorophosphate                                   BSTFA        N,O-bis(trimethylsilyl)triflouoromethyl-                                       acetamide                                                         Cbz          benzyloxycarbonyl                                                 DCC          1,3-dicyclohexylcarbodiimide                                      DEAD         diethyl azodicarboxylate                                          DEC          1-(3-dimethylaminopropyl)-3-                                                   ethylcarbodiimide hydrochloride                                   DIEA         diisopropylethylamine                                             DCHA         dicyclohexylamine                                                 DCM          dichloromethane                                                   DMAP         4-dimethylaminopyridine                                           DMF          N,N-dimethyl formamide                                            EtOAc        ethyl acetate                                                     EtOH         ethyl alcohol                                                     HOBt         1-hydroxybenzotriazole                                            IBCF         iso-butyl chloroformate                                           LAH          lithium aluminum hydride                                          NCS          N-chlorosuccinimide                                               NMM          N-methylmorpholine                                                PPh.sub.3    triphenylphosphine                                                pyr          pyridine                                                          TBTU         2-(1H-Benzotriazol-1-yl)-1,1,3,3-                                              tetramethyluronium tetrafluoroborate                              TFA          trifluoroacetic acid                                              THF          tetrahydrofuran                                                   ______________________________________                                    

A convenient method for the synthesis of the compounds of this invention utilizes a dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles to prepare the isoxazoline rings present in compounds of Formula I (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocycles 1990, 30, 719).

Scheme I describes one synthetic sequence to the compounds of the second embodiment of this invention. An appropriately substituted hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J. Org. Chem. 1980, 45, 3916). The resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline. Alternatively, the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508). Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the desired acids. Intermediates containing alkali-sensitive functionality, such as nitrile, may be deesterified with excellent chemoselectivity using sodium trimethylsilanolate according to the procedure of Laganis and Ehenard (Tetrahedron Lett. 1984, 25, 5831). Coupling of the resulting acids to an appropriately substituted α- or β-amino ester using standard coupling reagents, such as DCC/HOBt, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions followed by ester saponification (LiOH, THF/H₂ O). ##STR47##

An example of a related method of preparation for compounds within the second embodiment of the present invention is illustrated in Scheme Ia. Conversion of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid to the corresponding amidine, followed by protection as the Boc-derivative and saponification provides 3-(4-Boc-amidinophenyl)isoxazolin-5-ylacetic acid which is coupled with P-amino acid esters as shown. Deprotection provides the desired isoxazolinylacetyl-β-aminoalaninyl esters. Saponification as described above gives the free acids. ##STR48##

A further example of the synthesis of compounds within the second embodiment is shown in Scheme Ib. Cycloaddition of commerically available 4-cyanostyrene and t-butyl-3-oxoproprionate oxime using the method -described by Gree et al. (Bioorganic and Med. Chem. Lett. 1994, 253) provides t-butyl [5-(4-cyanophenyl)isoxazolin-3-yl]acetate. Using the procedures described above, this intermediate is converted to compounds of formula I wherein the isoxazoline ring is in the reverse orientation with respect to the compounds prepared via Schemes I and Ia. ##STR49##

Additional isoxazolinyl acetates useful as starting materials for the preparation of compounds of Formula I, wherein V is -(phenyl)-Q- and Q is other than a single bond, can be prepared by cycloaddition of a suitably substituted chloro or bromooxime with an ester of vinyl acetic acid as shown in Scheme Ic using literature methods or modifications thereof. (D. P. Curran & J. Chao, J. Org. Chem. 1988, 53, 5369-71; J. N. Kim & E. K. Ryu, Heterocycles 1990, 31, 1693-97). ##STR50##

The compounds of the present invention where R² or R³ is e.g. alkoxycarbonyl may be prepared by reacting the free amidines, amines or guanidines with an activated carbonyl derivative, such as an alkyl chloroformate. In compounds of the second embodiment, the conversion of the free amines, amidines and guanidines to such acyl-nitrogen groups may optionally be performed prior to coupling an isoxazoline acetic acid with e.g β-amino acids, as illustrated in Scheme Ia.

The compounds of the present invention wherein Y is an oxyalkoxy group, e.g. alkoxycarbonyloxyalkoxy, may be prepared by reacting a suitably protected carboxylic acid of Formula I with an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.

The appropriately substituted racemic β-amino acids may be purchased commercially or, as is shown in Scheme II, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299). Racemic β-substituted-β-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous acid in ethanol (Scheme I, Method 2) or by reductive amination of β-keto esters as is described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58, 7948-51.) Enantiomerically pure β-substituted-β-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding α-amino acids as shown in Scheme II, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme II, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive treatise on the preparation of β-amino acid derivatives may be found in patent application WO 9307867, the disclosure of which is hereby incorporated by reference. ##STR51##

The synthesis of N² -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981).

The appropriately substituted pyrrolidine-, piperidine- and hexahydroazepineacetic acids may be prepared using a number of methods. The pyrrolidines are conveniently prepared using an Arndt-Eistert homologation of the corresponding proline as shown in Scheme III, Method 1 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within). The piperidines can be prepared by reduction of the corresponding pyridine as shown in Scheme III, Method 2. The hexahydroazepines are prepared by reduction of the corresponding vinylogous amide using sodium cyanoborohydride as depicted in Scheme III, Method 3. ##STR52##

Many additional appropriately substituted heterocycles are available commercially or can be readily modified by procedures known by one skilled in the art. Appropriately substituted morpholines can be prepared from amino acids via the sequence of steps depicted in Scheme IIIa, method 1 (see Brown, et. al. J. Chem. Soc. Perkin Trans I 1987, 547; Bettoni, et. al. Tetrahedron 1980, 36, 409; Clarke, F. H. J. Org. Chem. 1962, 27, 3251 and references therein.) N-ethoxycarbonylmethyl-1,2-diazaheterocyles are prepared by condensation of suitably substituted dibromides with benzylhydrazine followed by Mitsunobu reaction with ethyl hydroxyacetate and deprotection as shown in Scheme IIIa, method 2 (see Kornet, et. al. J. Pharm. Sci. 1979, 68, 377.; Barcza, et. al. J. Org. Chem. 1976, 41, 1244 and references therein.) ##STR53##

A general synthetic protocol to the compounds of the first embodiment of this invention is depicted in Scheme IV. Coupling of a suitable Boc-protected amino alcohol to an appropriately substituted phenol under Mitsunobu conditions (see Mitsunobu, Synthesis 1981, 1) is followed by oximation using hydroxylamine hydrochloride in 1:1 ethanol/pyridine. Isoxazoline formation, ester saponification and Boc-deprotection (33% TFA/DCM) then affords the compounds of this invention in good overall yield. ##STR54##

The synthesis of the spiro-fused isoxazolinyl imides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme V. Dipolar cycloaddition of an oximinoyl chloride with a α-methylene diester affords an isoxazolinyl diester, which is deesterified using the silanolate method. Dehydration to the anhydride according to Ishihara, et al. (Chem. Pharm. Bull. 1992, 40, 1177-85) followed by imide formation using an appropriately substituted amino ester affords the spirocycle. Alternatively, the imide may be prepared directly from the isoxazoline diester according to Culbertson, et al. (J. Med. Chem. 1990, 33, 2270-75). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR55##

The synthesis of the spiro-fused isoxazolinyl amides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VI. Dipolar cycloaddition of an oximinoyl chloride with a α-methylene lactone affords the isoxazolinyl lactone, which is reacted with an appropriate amino ester to afford the amide (see The Chemistry of the Amides (Zabicky, ed.), p 96, Interscience, New York, 1970; Prelog, et al., Helv. Chim. Acta 1959, 42, 1301; Inubushi, et al., J. Chem. Soc., Chem. Commun. 1972, 1252). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR56##

The synthesis of the spiro-fused isoxazolinyl cycloalkenes of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VII. Dipolar cycloaddition of an oximinoyl chloride with an appropriately substituted α-methylene lactone affords the isoxazolinyl lactone. The lactone is then reacted with an appropriate lithium dimethyl alkylphosphonate, followed by PCC oxidation. The resulting diketophosphonate undergoes an intramolecular Wittig reaction in the presence of K₂ CO₃ /18-crown-6 according to the method described by Lim and Marquez (Tetrahedron Lett. 1983, 21, 5559). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR57##

The dipolarophiles used to prepare the compounds of this invention may be prepared by numerous methods. The ω-alkenoic ester class of dipolarophile may be purchased commercially or prepared by oxidation of the corresponding ω-alkenols by the method of Corey and Schmidt (Tetrahedron Lett. 1979, 399, Scheme VIII, Method 1). The α-methylene diester and α-methylene lactone class of dipolarophile may be purchased commercially or can be prepared by numerous methods from the corresponding diester (see Osbond, J. Chem. Soc. 1951, 3464; Ames and Davey, J. Chem,. Soc 1958, 1794; Vig, et al., Ind. J. Chem. 1968, 6, 60; Grieco and Hiroi, J. Chem, Soc., Chem, Commun. 1972, 1317, Scheme VIII, Method 2). The 3-(styryl)propionic ester class of dipolarophile may be prepared by palladium-catalyzed cross coupling of the appropriately substituted bromo- or iodohydrocinnamic acid to a vinylmetal species according to methods cited within Mitchell (Synthesis 1992, 803) and Stille (Angew. Chem. Int. Ed. Engl. 1986, 25, 508, Scheme VIII, Method 3). ##STR58##

Compounds of Formula I wherein b is a double bond can be prepared using one of the routes depicted in Scheme IX. Bromination followed by subsequent dehydrobromination of a suitably substituted methyl 3-(cyanophenyl)isoxazolin-5-ylacetate, prepared as described above, using the method of Elkasaby & Salem (Indian J. Chem. 1980, 19B, 571-575) provides the corresponding isoxazole intermediate. Alternately, this intermediate can be obtained by 1,3-dipolar cycloaddition of a cyanophenylnitrile oxide (prepared from the corresponding chlorooxime as described in Scheme I) with an appropriate alkyne to give the isoxazole directly. Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the acetic acids. Coupling of the resulting acids to an appropriately substituted α- or β-amino ester using standard coupling reagents, such as TBTU, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions to give the prodrug esters. Saponification gives the acids. ##STR59##

Compounds of Formula I wherein R¹ is (R²) (R³)N(R² N═)CN(R²)-- and V is phenylene are prepared as illustrated in Scheme X. Cycloaddition of an appropriately N-protected aminophenylaldoxime with vinyl acetic acid, t-butyl ester, using the conditions described above provides t-butyl [3-(4-t-butyloxycarbonylaminophenyl)isoxazolin-5-yl]acetate. Hydrolysis of the ester with lithium hydroxide provides the free acid which can be coupled with a suitably substituted methyl 3-aminopropionate as previously described. After deprotection, the aniline is converted to the corresponding guanidine using the method described by Kim et al. (Tetrahedron Lett. 1993, 48, 7677). A final deprotection step to remove the BOC groups provides guanidino compounds of Formula I. ##STR60##

An example of the preparation of compounds of the second embodiment wherein R¹ -U is a benzamide is illustrated in Scheme XI. Conversion of the 3-(4-cyanophenyl)isoxazolin-5-yl-β-aminoalaninyl esters to the amides can be accomplished by reaction of the nitrile with an appropriate alcohol under acidic conditions. (J. Med. Chem. 1991, 34, 851.) The substituted amides can be accessed by allowing the 3-(4-cyanophenyl)isoxazolin-5-yl-β-aminoalaninyl esters to react with an appropriate halogenated compound (Synthesis, 1978, 303. Saponification as described above gives the free acids. ##STR61##

The compounds of the invention where U is a pyridyl may be prepared by several methods. 2-Amino-4-pyridyl analogs can be easily accessed from readily available 2-bromo-4-pyridylcarboxaldehyde (Corey, E. J. et. al. Tetrahedron Lett. 1983, 32, 3291). The desired amino compound can be suitably introduced by displacement of the bromo substituent with a suitable ammonia source or alternatively with sodium azide followed by reduction via standard techniques known to those in the art. 2-Amidino-5-pyridyl analogs can be accessed from 2-bromo-5-pyridylcarboxaldehyde by displacement of the bromide at an appropriate stage in the synthesis with KCN. Conversion of the nitrile to the requisite amidine then affords the desired products. 6-Amino-3-pyridyl analogs can be easily accessed (according to the method described for the preparation of 2-amino-5-pyridyl analogs) from 6-chloro-3-pyridylcarboxaldehyde. This was obtained in part from 6-chloro-3-pyridylcarboxylic acid (Aldrich) via techinques known in the art. 6-Amidino-3-pyridyl analogs can be readily accessed from 6-chloro-3-pyridylcarboxaldehyde via techniques described for 2-amidino-5-pyridylanalogs.

The preparation of quinuclidine carboxaldehyde starting materials may be done as follows. 4-Cyanoquinuclidine prepared by the method of Kanai, T. et al, (Het., 1992, 34, 2137), can be converted to quinuclidine-4-carboxaldehyde by standard conditions and homologated by the method of (Tetrahedron Lett. 1987, 28, 1847) to the desired aldehyde. Conversion of the aldehyde to the oxime followed by chlorination to the chlorooxime should then afford the key quinuclidine chlorooxime which can then be further elaborated to the desired compounds.

The synthesis of spiro-fused isoxazolinyl amines of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme XII. Dipolar cycloaddition of a suitable oxime with a suitably protected methylenecycloamine, prepared by methods known in the literature (De Amici, M.; Frolund, B.; Hjeds, H.; Krogsgaard-Larson, P. Eur. J. Med. Chem. 1991, 26, 625; Mimura, M., et. al. Chem. Pharm. Bull. 1993, 41, 1971; Labouta, I. M.; Jacobsen, P.; Thorbek, P.; Krogsgaard-Larson, P.; Hjeds, H. Acta Chem. Scand., Ser. B 1982, 36, 669), yields the spirocyclic amine after deprotection. This amine can be functionalized with a serine beta-lactone (Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105) providing an optically active product. Alternatively, the amine can be reacted with a 3-iodo or 3-chloroalanine derivative (I: Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471; Cl: Bigge, C. F.; Wu J.-P.; Druumond, J. R. Tetrahedron Lett. 1991, 32, 7659; Benoiton, L. Can. J. Chem. 1968, 46, 1549) to give a racemic product. ##STR62## The cycloaddition can also be performed after the introduction of the propionyl side chain as shown in Scheme XIII. ##STR63##

The compounds of Tables 12 and 13 were made using combinatorial synthetic methodology as shown in Scheme XIV. Thus, a resin was derivatized and to it was coupled the protected 2,3-diaminoproprionate. Following deprotection of N³, the desired isoxazoline carboxylic acid was coupled to N³. The final product was removed from once the terminal amine of the isoxazoline carboxylic acid was converted to its desired form. ##STR64##

The compounds of this invention and their preparation can be further understood by the following procedures and examples, which exemplify but do not constitute a limit of their invention.

EXAMPLE 1 3- (4-[2-Piperidin-4-yl)ethoxy]-phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

Part A. Preparation of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol

This material was prepared from 4-piperidine-2-ethanol according to European Patent Application Publication Number 478363 A2.

Part B. 4-[2-(N-t-Butyloxycarbonylpiperidinyl-4-yl)ethoxy]benzaldehyde

To a solution of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol (7.71 g, 33.6 mmol), 4-hydroxybenzaldehyde (4.11 g, 33.6 mmol) and PPh₃ (8.82 g, 33.6 mmol) in THF (60 mL) at -20° C. was added a solution of DEAD (5.3 mL, 33.7 mmol) in THF (30 mL) over 2 hours. During the addition, a deep red solution resulted, which changed to a golden color upon warming to room temperature overnight (18 hours). At this time the solution was concentrated and redissolved in EtOAc. It was then washed with water, 0.1M HCl, 1M NaOH, sat. NaCl and dried (MgSO₄). Concentration gave a solid (˜20 g), which was purified using flash chromatography (10-20-30-40-50% EtOAc/hexanes step gradient), affording 7.82 g (70%) of the desired ether after pumping to constant weight; mp 76.4-79.7° C.; ¹ H NMR (300 MHz, CDCl₃) δ 9.88 (s 1H), 7.83 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 4.10 (bd, J=12.8 Hz, 2H), 4.04 (t, J=6.6 Hz 2H), 2.69 (bt, 2H), 1.84 (m, 2H), 1.70 (bd J=14.3 Hz, 2H), 1.46 (s, 9H, overlapped with m, 2H), 1.10 (m, 2H).

Part C. 4-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime

To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldehyde (3.16 g, 9.48 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (1.27 g, 18.3 mmol) and 2M NaOH (7 mL, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 hours). The mixture was brought to pH 4 using 1M HCl, followed by filtration and water wash. The crystals were dried under vacuum over P₂ O₅, affording 2.88 g (87%); mp: 114.4-116.1° C.; ¹ H NMR (300 MHz, CDCl₃) δ 8.09 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.10 (b, 2H), 4.03 (t, J=6.2 Hz 2H), 2.71 (bt, 2H), 1.73 (m, 4H), 1.46 (s, 9H), 1.19 (m, 2H).

Part D. 4-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoximinoyl Chloride

To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime (955 mg, 2.74 mmol) in DMF (5 mL) was added NCS (366 mg, 2.74 mmol) in 3 portions. After 3 hours, the solution was diluted with EtOAc and washed with water, sat. NaCl, dried (MgSO₄) and concentrated. The resulting solid was crystallized from ether/hexanes to give 548 mg (52%) of the oximinoyl chloride; mp. 119.3-119.9° C.; ¹ H NMR (300 MHz, CDCl₃) δ 8.37 (bs 1H), 7.77 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.12 (bd, J=13.2 Hz, 2H), 4.04 (t, J=6.2 Hz 2H), 2.72 (bt, J=12.1 Hz, 2H), 1.70 (m, 5H), 1.46 (s, 9H), 1.10 (m, 2H).

Part E. Methyl 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R, S)-isoxazolin-5-ylacetate

To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoximinoyl chloride (400 mg, 1.045 mmol) and methyl 3-butenoate (200 mg, 2.00 mmol) was added TEA (0.15 mL, 1.1 mmol). The resulting suspension was heated at reflux for 5 hours, cooled to room temperature and diluted with EtOAc. It was then washed with 0.1M HCl, water, sat. NaCl, dried (MgSO₄) and concentrated. The resulting solid was crystallized from DCM/hexanes to give 357 mg (77%) of the isoxazoline; mp: 139.1-140.9° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.59 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.08 (m, 1H), 4.10 (bd, J=13.2 Hz, 2H), 4.04 (t, J=5.9 Hz 2H), 3.73 (s, 3H), 3.53 (dd, J=16.5, 10.1 Hz, 1H), 3.10 (dd, J=16.8, 7.1 Hz, 1H), 2.88 (dd, J=16.1, 5.9 Hz, 1H), 2.71 (bt, J=12.8 Hz, 2H), 2.64 (dd, J=15.8, 7.7 Hz, 1H), 1.72 (m, 5H), 1.46 (s, 9H), 1.08 (m, 2H).

Part F. 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid

To a solution of methyl 3-[4-{2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetate (47 mg, 0.105 mmol) in THF (2 mL) was added 0.5M LiOH (1 mL, 0.5 mmol). The reaction was stirred at room temperature for 5 hours, then was acidified to pH 3 using 0.1M HCl. The mixture was washed with DCM and the combined organic fraction dried (MgSO₄) and concentrated. The resulting solid was crystallized from EtOAc/hexanes to give 34 mg (74%) of the carboxylic acid; mp: 169.1-170.6° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.60 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.10 (m, 1H), 4.08 (bd, 2H, overlapped with t, J=5.9 Hz 2H), 3.55 (dd, J=16.5, 10.2 Hz, 1H), 3.11 (dd, J=16.8, 7.0 Hz, 1H), 2.93 (dd, J=16.1, 6.2 Hz, 1H), 2.71 (m, 3H), 2.00 (m, 2H), 1.72 (m, 5H), 1.46 (s, 9H).

Part G. 3-(4-[2-(Piperidin-4-yl)ethoxylphenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

To a solution of 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetic acid (53 mg, 0.12 nmol) in DCM (2 mL) was added TFA (1 mL, 13 mmol). After 1.5 hours, the product was crystallized by the addition of ether, affording 33 mg (60%) of the amino acid; mp: 142.4-143.1° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.59 (dd, J=8.8, 2.6 Hz, 2H), 6.96 (dd, J=8.8, 2.6 Hz, 2H), 5.03 (m, 1H), 4.10 (m, 2H), 3.55 (ddd, J=16.8, 10.3, 2.2.Hz, 1H), 3.38 (bd, J=12.4 Hz, 2H), 3.16 (ddd, J=17.2, 7.7, 2.2 Hz, 1H), 2.98 (bt, J=13.2 Hz, 2H), 2.69 (m, 2H), 2.01 (bd, J=14.3 Hz, 2H), 1.91 (m, 1H), 1.80 (m, 2H), 1.46 (m, 2H).

EXAMPLE 4 2-[3-(4-[2-(Piperidin-4-yl)ethoxy]phenyl)isox-azolin-5-yl]-2-(S)-(benzyloxycarbonylamino)acetate, Trifluoroacetic Acid Salt

Part A. Benzyl 2-(S)-[[(benzyloxy)carbonyl]amino]-3-butenoate

This material was prepared from N-Cbz-l-glutamic acid α-benzyl ester according to Krol, et al. (J. Org. Chem, 1991, 728).

Part B. Benzyl (2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetate

To a solution of 4-[(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime (852 mg, 2.44 mmol) and benzyl l-2-[[(benzyloxy)carbonyl]amino]-3-butenoate (612 mg, 1.88 mmol) in DCM (10 mL) was added 5% NaOCl (common household bleach, 4 mL, 2.8 mmol). The mixture was rapidly stirred at room temperature for 22 hours, after which time it was diluted with water and DCM. After separation of the layers, the aqueous was washed with DCM (3x). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo, giving 1.4 g. Purification using flash chromatography (10% EtOAc/hexanes--30% EtOAc/hexanes) then afforded 886 mg (70%) of an oily product as a 2.5:1 mixture of the erythro and threo isomers; ¹ H NMR (400 MHz, CDCl₃) δ 7.50 (m, 2H), 7.34 (m, 5H), 7.23 (m, 5H), 6.87 (d, J=8.8 Hz, 2H), 5.47 (bd, 1H), 5.12 (m, 5H), 4.60 (m, 1H), 4.07 (m, overlapped with 4.03 (t, J=6.1 Hz, 4H) , 3.36 (m, 2H), 2.71 (bt, J=12.7 Hz, 2H), 1.70 (m, 5H), 1.45 (s, 9H), 1.18 (m, 2H); Anal. Calc. for C₃₈ H₄₅ N₃ O₈ : C, 67.93; H, 6.76; N, 6.26. Found: C, 67.95; H, 6.77; N, 6.17.

Part C. (2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid

A solution of benzyl (2S)-(5R,S)-[3-[4-{(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyl-oxy)carbonyl]amino}]acetate (875 mg, 1.302 mmol) in THF (5 mL) was saponified over 5 hours using 0.5M LiOH (3.5 mL) according to Example 1, Part F. To the crude product was added methanol, causing crystallization of one of the diastereomers. Filtration and pumping to constant weight gave 295 mg (39%); mp: 216.1° C.; ¹ H NMR (400 MHz, DMSO-d₆, 80° C.) δ 7.50 (d, J=8.9 Hz, 2H), 7.23 (s, 5H), 6.96 (d, J=8.9 Hz, 2H), 6.17 (bs, 1H), 4.99 (m, 3H), 4.07 (t, J=6.1 Hz, 2H), 3.90 (m, 3H), 3.35 (d, J=9.3 Hz, 2H), 2.72 (bt, J=12.4 Hz, 2H), 1.67 (m, 5H), 1.39 (s, 9H), 1.08 (m, 2H). The filtrate was concentrated in vacuo and pumped until constant weight was achieved, giving 200 mg (26%) of the carboxylic acids as a mixture of erythro- and threo-isomers; TLC (silica gel 60, 20% MeOH/CHCl₃) R_(f) =0.23, Mass Spectrum (ESI, e/z, relative abundance) 582 (M+H)⁺, 32%; 526 (M-C₄ H₉ +H₂)⁺, 100%; 482 (M-Boc+H₂)⁺, 91%).

Part D. (2S)-(5R,S)-[3-[4-{(2-Piperidin-4-yl)ethoxyl}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid (isomer A)

(2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic acid (23 mg, 0.039 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 15 mg (79%); mp: 302° C. (dec); ¹ H NMR (400 MHz, DMSO-d₆, 60° C.) δ 7.57 (d, J=8.8 Hz, 2H), 7.30 (s, 5H), 6.99 (d, J=8.8 Hz, 2H), 5.05 (s, 2H, coincident with m, 1H), 4.35 (d, J=4.9 Hz,, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.52 (dd, J=17.3, 10.7 Hz, 1H), 3.26 (m, 3H), 2.88 (dt, J=12.7, 2.7 Hz, 2H), 1.88 (bd, J=14.4 Hz, 2H), 1.80 (m, 1H), 1.72 (m, 2H), 1.38 (m, 2H).

Part D'. (2S)-(5R,S)-[3-[4-{(2-Piperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid, Trifluoroacetic Acid Salt (isomer B)

(2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic acid (177 mg, 0.304 nmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 3 mg (2%) of the TFA salt; mp: >400° C.; ¹ H NMR (400 MHz, DMSO-d₆, 60° C.) δ 8.48 (bs,0.5H) , 8.15 (bs, 0.5H), 7.55 (d, J=8.9 Hz, 2H), 7.30 (m, 5H), 6.97 (d, J=8.9 Hz, 2H), 5.05 (s, 2H), 4.96 (m, 1H), 4.33 (m, 1H) , 4.07 (t, J=6.3 Hz, 2H) , 3.38 (m, 2H) , 3.26 (bd, J=12.0 Hz, 2H), 2.87 (m, 2H), 1.86 (bd, J=14.2 Hz, 2H), 1.78 (m, 1H), 1.70 (apparent q, J=6.3 Hz, 2H), 1.36 (bq, J=13.2 Hz, 2H).

EXAMPLE 6 3-(3-[4- (Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt

Part A. Ethyl N-t-Butyloxycarbonylpiperidine-4-carboxylate

To a stirred solution of ethyl isonipecotate (20.01 g, 0.1273 mol) in EtOAc (100 mL) at 0° C. was added dropwise a solution of Boc₂ O (27.76 g, 0.1272 mol) in EtOAc (50 mL). The mixture was allowed to warm to room temperature overnight. After 20 hours, the mixture was washed with water, 0.1M HCl, sat. NaHCO₃, sat. NaCl and dried (MgSO₄). Concentration and pumping under vacuum to constant weight gave 32.54 g (99%) of the desired carbamate as a mobile oil; ¹ H NMR (300 MHz, CDCl₃) δ 4.13 (q, J=7.0 Hz, 2H), 4.03 (dm, J=13.6 Hz 2H), 2.81 (m, 2H), 2.41 (m, 1H), 1.86 (dm, J=13.6 Hz, 2H), 1.62 (m, 2H), 1.44 (s, 9H), 1.24 (t, J=7.0 Hz, 3H).

Part B. N-t-Butyloxycarbonylpiperidin-4-ylmethanol

To a solution of ethyl N-t-butyloxycarbonylpiperidine-4-carboxylate (32.34 g, 0.1257 mol) in THF (100 mL) at 0° C. was added dropwise 1M LAH in THF (87.9 mL, 0.0879 mol). After 2 hours, excess hydride was quenched by the addition of water (3.2 mL), 2M NaOH (3.2 mL) and water (10 mL). The mixture was filtered, washed with EtOAc and the filtrate washed with water, sat. NaCl, dried (MgSO₄) and concentrated. Pumping to constant weight gave 22.72 g (84%); mp: 79.2-81.1° C.; ¹ H NMR (300 MHz, CDCl₃) δ 4.12 (bd, J=12.8 Hz 2H), 3.49 (d, J=6.2 Hz, 2H), 2.68 (dt, J=13.2, 1.8 Hz, 2H), 1.69 (m, 3H), 1.44 (s, 9H, overlapped with m, 1H), 1.14 (m, 2H).

Part C. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldehyde

To N-t-butyloxycarbonylpiperidin-4-ylmethanol (7.87 g, 36.5 mmol), p-hydroxybenzaldehyde (4.46 g, 36.5 mmol) and PPh₃ (9.59 g, 36.5 mmol) in THF (100 mL) at -20° C. was added DEAD (5.75 mL, 36.5 mmol) in THF (50 mL) according to Example 1, Part B, affording 8.14 g (70%); mp: 115.6-116.8° C.; ¹ H NMR (300 MHz, CDCl₃) δ 9.86 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.15 (bd, J=13.2 Hz 2H), 3.87 (d, J=6.6 Hz, 2H), 2.74 (dt, J=12.4, 1.8 Hz, 2H), 1.97 (m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.27 (dq, J=12.1, 4.0 Hz, 2H).

Part D. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoxime

A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3x), water, sat. CuSO₄ (2x), water, sat. NaCl, dried (MgSO₄) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1-141.8° C.; ¹ H NMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).

Part E. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoximinoyl Chloride

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoxime (3.19 g, 9.54 mmol) in DMF (10 mL) was reacted with NCS (1.27 g, 9.51 mmol) for 18 hours according to Example 1, Part D to afford the hydroximinoyl chloride (1.17 g, 33%); mp: 178.0-179.8° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.75 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.17 (bd, J=12.4 Hz, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.74 (dt, J=12.8, 1.8 Hz, 2H), 1.95 (m, 1H), 1.81 (bd, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.27 (dq, J=12.5, 4.0 Hz, 2H).

Part F. Methyl 3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionate

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (738 mg, 2.00 mmol), methyl 4-pentenoate (230 mg, 2.02 mmol) and TEA (0.28 mL, 2.0 mmol) were heated at reflux for 1 hour according to Example 1, Part E. Crystallization from ether/hexanes afforded 537 mg (60%). mp: 97.9-99.9° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz,2H), 4.74 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.67 (s, 3H), 3.40 (dd, J=16.5, 10.2 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.73 (dt, J=13.2, 1.1 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H), 1.98 (q, J=7.0 Hz, 2H, overlapping m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.4, 3.7 Hz, 2H).

Part G. 3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid

Methyl 3-(3-[4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionate (250 mg, 0.560 mmol) was saponified using 0.5M LiOH (2 mL, 1 mmol) in THF (2 mL). The reaction was stirred at room temperature for 3 hours, according to Example 1, Part F. The resulting solid was crystallized from DCM/hexanes to give 163 mg (67%) of the carboxylic acid; mp: 146.5-147.7° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.75 (m, 1H), 3.81 (d, J=6.2 Hz, 2H), 3.41 (dd, J=16.5, 10.3 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.75 (bt, J=12.4 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 1.97 (m, 3H), 1.81 (bd, J=12.1 Hz, 2H), 1.45 (s, 9H), 1.24 (m, 2H).

Part H. 3-(3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt

3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic acid (103 mg, 0.238 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 88 mg (83%) of the TFA salt; mp: 179.1-181.8° C.; ¹ H NMR (400 MHz, MeOH-d₄) δ 7.60 (d, J=9.0 Hz, 2H) , 6.97 (d, J=9.0 Hz, 2H), 4.73 (m, 1H), 3.94 (d, J=6.1 Hz, 2H), 3.46 (m, 3H), 3.06 (m, 3H), 2.45 (dt, J=7.3, 1.2 Hz, 2H), 2.16 (m, 1H), 2.08 (bd, J=15.4 Hz, 2H), 1.94 (q, J=6.6 Hz, 1H), 1.64 (dq, J=14.2, 4.2 Hz, 2H).

EXAMPLE 7 3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

Part A. Methyl 3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetate

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (412 mg, 1.12 mmol), methyl 3-butenoate (200 mg, 2.00 mmol) and TEA (0.18 mL, 1.3 mmol) were heated at reflux for 2 hours according to Example 1, Part E. Crystallization from chloroform/cyclohexane afforded 329 mg (68%). mp: 97.9-99.9° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.58 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz,2H), 5.04 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 3.54 (dd, J=16.8, 10.3 Hz, 1H), 3.08 (dd, J=16.8, 7.3 Hz, 1H), 2.86 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=12.8, 1.8 Hz, 2H), 2.62 (dd, J=15.8, 7.7 Hz, 1H), 1.95 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.25 (dq, J=12.8, 4.4 Hz, 2H).

Part B. 3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid

Methyl 3-[4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetate (329 mg, 0.762 mmol) was saponified using 0.5M LiOH (3 mL, 1.5 mmol) in THF (5 mL). The reaction was stirred at reflux for 4 hours, according to Example 1, Part F to give 72 mg (22%) of the carboxylic acid; mp: 164.0-164.8° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.58 (d, J=8.8 Hz, 2H) , 6.88 (d, J=8.8 Hz, 2H), 5.07 (m, 1H), 4.15 (bd, J=13.6 Hz, 2H), 3.82 (d, J=6.2 Hz, 2H), 3.53 (dd, J=16.8, 10.3 Hz, 1H), 3.10 (dd, J=16.8, 7.0 Hz, 1H), 2.91 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=14.6, 1.8 Hz, 2H), 2.68 (dd, J=16.1, 7.3 Hz, 1H), 1.97 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.8, 4.4 Hz, 2H).

Part C. 3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic acid (72 mg, 0.172 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 64 mg (94%) of the TFA salt; mp: 220° C. (dec); ¹ H NMR (300 MHz, MeOH-d₄) δ 7.61 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 5.04 (m, 1H), 3.95 (d, J=5.9 Hz, 2H), 3.56 (dd, J=17.2, 10.2 Hz, 1H), 3.45 (bd, J=12.8 Hz, 2H), 3.18 (dd, J=17.2, 7.3 Hz, 1H), 3.04 (dt, J=10.2, 2.9 Hz, 2H), 2.69 (m, 2H), 2.18 (m, 1H), 2.08 (bd, J=14.6 Hz, 2H) 1.63 (bq, 2H).

EXAMPLE 8 3-[4-(2-Piperidin-4-yl)ethoxyphenyl]-(5R,S)-isoxazolin-5-ylpropionic Acid, Trifluoroacetic Acid Salt

This material was prepared analogously to Example 1, giving the desired material; mp: 114.8-115.7° C.; ¹ H NMR (300 MHz, CD₃ OD) δ 7.59 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 4.72 (m, 1H), 4.07 (t, J=5.9 Hz, 2H), 3.47 (dd, J=16.8. 10.2 Hz, 1H), 3.37 (dd, J=16.8, 7.7 Hz, 1H), 2.98 (m, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.01 (bd, J=15.0 Hz, 2H), 1.93 (m, 3H), 1.80 (m, 2H), 1.44 (m, 2H).

EXAMPLE 9 erythro- and-threo-3-[3-[4-[(piperidin-4-yl)methoxy]phenyl]isoxazolin-5-yl{[butanesulfonyl]amino]propionate, Trifluoroacetic Acid Salt

Part A. Dicyclohexylammonium d,l-2-[(Butanesulfonyl)-aminol-4-pentenoic acid,

To a suspension of d,l-2-amino-4-pentenoic acid (2.54 g, 22.06 mmol) in acetonitrile (35 mL) was added BSTFA (7.3 mL, 27.5 mmol). The suspension was heated at 55° C. for 2 hours, after which time a golden yellow solution resulted. To this solution was added pyridine (2.2 mL, 27.2 mmol) and n-butanesulfonyl chloride (3.0 mL, 23.1 mmol). The mixture was heated at 70° C. for 20 hours, then cooled to room temperature. Concentration in vacuo afforded a brown oil, to which was added 15% KHSO₄ (5 mL). The mixture was stirred for 1 hour and shaken with EtOAc (3x). The combined organic extracts were washed with sat. NaCl, dried (MgSO₄), concentrated and the resulting oil dissolved in ether (5 mL). To this solution was added DCHA (4.38 mL, 22.0 mmol), causing immediate precipitation of the dicyclohexylammonium salt. The solid was collected by filtration and pumped to constant weight, giving 8.42 g (92%); mp: 207.1-208.6° C.; ¹ H NMR (400 MHz, MeOH-d₄) δ 5.84 (m, 1H), 5.09 (dm, J=17.1.Hz, 1H), 5.04 (dm, J=10.2 Hz, 1H), 3.80 (dd, J=7.1, 5.1 Hz, 1H), 3.18 (m, 2H), 3.02 (m, 2H), 2.49 (m, 2H), 2.06 (m, 4H) , 1.78 (m, 8H), 1.55 (m, 12H), 0.94 (t, J=7.3 Hz).

Part B. Methyl d,l-2-[(Butanesulfonyl)amino]-4-pentenoate

To a solution of dicyclohexylammonium d,l-2-[(butanesulfonyl)amino]-4-pentenoate (8.36 g, 20.07 mmol) in MeOH (50 mL) was added HCl-saturated MeOH (50 mL). The resulting suspension was stirred at room temperature for 18 hours, diluted with ether, and filtered. Concentration of the filtrate in vacuo was followed by the addition of ether, a second filtration, and washing of the filtrate with 0.1M HCl, sat. NaHCO₃, sat. NaCl. The solution was dried over anhydrous MgSO₄, concentrated and placed under vacuum until constant weight to give 4.49 g (90%) of the desired ester as a light brown oil; ¹ H NMR (300 MHz, CDCl₃) δ 5.68 (m, 1H), 5.19 (bd, J=1.5 Hz, 1H), 5.15 (m, 1H), 4.78 (bd, J=8.4 Hz, 1H), 4.20 (dt, J=8.8, 5.8 Hz, 1H), 3.77 (s, 3H), 2.99 (m, 2H), 2.54,(t, J=6.6 Hz, 2H), 1.76 (m, 2H), 1.42 (sextuplet, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H)

Part C. Methyl erythro- and-threo-3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{(butanesulfonyl]amino})propionate

To a solution of 4-[(N-t-butyloxycarbonylpiperidin-4-yl)methoxy]benzaldoxime (2.680 g, 8.01 mmol), methyl d,l-2-[(butanesulfonyl)amino]-4-pentenoate (2.000 g, 8.02 mmol) and TEA (0.11 mL, 0.79 mmol) in THF (10 mL) was added a 5% solution of NaOCl (common household bleach, 15 mL, 10.5 mmol). The resulting mixture was rapidly stirred at room temperature for 20 hours. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous portion was washed with EtOAc, and the combined organic fraction washed with sat. NaCl and dried over MgSO₄. Concentration in vacuo afforded a light brown oil (4.8 g), which was purified using flash chromatography (0-50% EtOAc/hexanes in 5 steps), giving four components. The least polar of these materials (fractions 8-11) was determined by ¹ H NMR to be the starting olefin (1.520 g, 76%). The next component isolated in order of increasing polarity (fractions 12-15) was determined by ¹ H NMR to be the starting oxime (1.423 g, 53%). The next component off of the column (fraction 20) was determined to be the faster of the two diastereomers (317 mg). This material had co-eluted with an impurity having a ¹ H NMR profile similar to the starting oxime and appeared to be approximately 50% pure. The most polar component isolated (fractions 22-25) was assigned as the second diastereomer (395 mg, 8%); mp:.127.5-129.3° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.6 Hz, 2H) , 6.87 (d, J=8.6 Hz, 2H), 5.25 (d, J=9.5 Hz, 1H), 4.87 (m, 1H), 4.35 (dt, J=9.2, 3.7 Hz, 1H), 4.15 (bs, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.78 (s, 3H), 3.49 (dd, J=16.5, 10.3 Hz, 1H), 3.05 (t, J=7.7 Hz, 2H), 2.97 (dd, J=16.5, 7.0 Hz, 1H), 2.73 (bt, J=12.1 Hz, 2H), 2.21 (m, 1H), 1.94 (m, 2H), 1.82 (m, 4H), 1.45 (s, 9H), 1.24 (m, 3H), 0.92 (t, J=7.3 Hz, 3H).

Part D. 3-(3- [4-{(Butyloxycarbonylpiperidin-4-yl)methox-y}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})-propionic Acid (More Polar Diastereomer)

A solution of methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate more polar diastereomer (200 mg, 0.344 mmol) in THF (1 mL) was saponified using 0.5M LiOH (1 mL, 0.5 mmol) over 4 hours as per Example 1, Part F. The crude carboxylic acid was crystallized from EtOAc/hexanes, affording 77 mg (39%) of the desired material; mp: 137.3-139.0° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.45 (d, J=9.5 Hz, 1H), 4.92 (m, 1H), 4.37 (m, 1H), 4.15 (b, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.47 (dd, J=16.5, 9.9 Hz, 1H), 3.08 (t, J=8.1 Hz, 2H), 3.01 (dd, J=16.5, 7.0 Hz, 1H), 2.74 (bt, J=12.1 Hz, 2H), 2.26 (m, 1H), 2.01 (m, 2H), 1.81 (m, 4H), 1.45 (s, 9H, overlapped with m, 1H), 1.24 (m, 3H) , 0.91 (t, J=7.3 Hz, 3H).

Part D'. 3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})-propionic Acid (Less Polar Diastereomer)

A solution of the impure methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate less polar diastereomer (309 mg) in THF (5 mL) was saponified using 0.5M LiOH (2 mL, 1 mmol) over 6 hours as per Example 1, Part F. The crude carboxylic acid was purified using flash chromatography (CHCl₃ --5-15% MeOH/CHCl₃ step gradient) followed by crystallization from EtOAc/hexanes, affording 169 mg of the desired material; mp: 155° C. (dec); ¹ H NMR (400 MHz, DMSO-d₆, 80° C.) δ 7.56 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.80 (m, 1H), 3.96 (bd, J=13.2 Hz, 2H), 3.90 (d, J=6.3 Hz, 2H), 3.77 (bs, 3H), 3.52 (t, J=7.8 Hz, 1H), 3.38 (dd, J=14.4, 10.0 Hz, 1H), 2.98 (t, J=7.8 Hz, 2H), 2.76 (dt, J=12.2, 1.7 Hz, 2H), 1.95 (m, 2H), 1.75 (m, 4H), 1.41 (s, 9H), 1.38 (d, J=7.6 Hz, 1H), 1.25 (m, 4H), 0.88 (t, J=7.3 Hz, 3H).

Part E. 3-(3-[4-{(Piperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic Acid, Trifluoroacetic Acid Salt (More Polar Diastereomer)

3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic acid more polar diastereomer(40 mg, 0.070 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G. Recrystallization from methanol then afforded 4 mg (10%) of the TFA salt; mp: 263.5° C. (dec).

Part E'. 3-(3-[4-{(Piperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino}propionic Acid, Trifluoroacetic Acid Salt (Less Polar Diastereomer)

3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic acid less polar diastereomer(98 mg, 0.173 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 40 mg of the TFA salt. Recrystallization from methanol then afforded 28 mg (29%) of the pure amino acid; mp: 239.4-240.7° C.

EXAMPLE 33 4-Carboxymethyl-3-[4- (2-piperidin-4-yl)ethoxyphenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

This material was prepared analogously to Example 1, giving the desired material; mp: 141.4° C. (dec); ¹ H NMR (400 MEz, CD₃ OD, 60° C.) δ7.60 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 3.84 (d, J=17.3 Hz, 1H), 3.66 (s, 3H), 3.59 (d, J=17.3 Hz, 1H), 3.38 (bd, J=12.9 Hz, 1H), 3.24 (t, J=1.7 Hz, 2H), 3.21 (dm, J=20.3 Hz, 1H), 3.04 (d, J=1.5 Hz, 2H), 3.00 (dt, J=12.9, 2.9 Hz, 2H), 2.02 (bd, J=14.4 Hz, 2H), 1.95 (m, 1H), 1.81 (m, 2H), 1.48 (m, 2H).

EXAMPLE 43 N-[3-(4-Amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(R,S)-3-amino-3-phenylpropanoic Acid

Part A: 4-Cyanobenzaldoxime

This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P₂ O₅ afforded 1.46 g (100%) of the desired oxime; mp: 167.8-169.4° C.

Part B: Methyl 3-(3-Butenoyl)amino-3-phenylpropionate

To a solution of vinylacetic acid (861 mg, 10.0 mmol), methyl 3-amino-3-phenylpropionate hydrochloride (2.37 g, 11.0 mmol) and TEA (1.6 mL, 12 mmol) in DCM (20 mL) at -10° C. was added DEC (2.11 g, 11.0 mmol). The resulting mixture was stirred at -10° C. for 15 hours. The mixture was then washed with water, 0.1 M HCl, sat. NaHCO₃, sat. NaCl and dried over anhydrous MgSO₄. Concentration in vacuo followed by pumping until constant weight gave 2.36 g (95%) of the desired amide as a golden oil of suitable purity for further reaction; ¹ H NMR (300 MHz, CDCl₃) δ7.28 (m, 5H), 6.78 (bd, J=7.7 Hz, 1H), 5.95 (m, 1H), 5.43 (dt, J=8.4, 5.9 Hz, 1H), 5.25 (m, 2H), 3.61 (s, 3H), 3.04 (d, J=7.0 Hz, 2H), 2.88 (dq, J=15.0, 5.9 Hz, 2H).

Part C: Methyl 3(R,S)-{5(R, S)-N-[3-(4-Cyanophenyl)isoxazolin-5-ylacetyl]amino)-3-phenylpropanoate

To a solution of methyl 3-(3-butenoyl)amino-3-phenylpropionate (816 mg, 3.30 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 438 mg, 3.00 mmol) in CH₂ Cl₂ (10 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 5.3 mL, 3.5 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH₂ Cl₂. The combined organic was dried (MgSO4) and concentrated in vacuo. The crude product was then purified using flash chromatography (70% EtOAc/hexanes), affording 731 mg (62%) of the desired isoxazoline as a 1:1 mixture of diastereomers; ¹ H NMR (300 MHz, CDCl₃) δ7.74 (m, 8H), 7.29 (m, 10H), 6.92 (bm, 2H), 5.42 (m, 2H), 5.16 (m, 2H), 3.64 (s, 3H), 3.60 (s, 3H), 3.48 (m, 2H), 3.26 (dd, J=17.3, 7.7 Hz, 1H), 3.15 (dd, J=16.8, 8.1 Hz, 1H), 2.85 (m, 2H), 2.69 (m, 2H).

Part D: Methyl 3(R,S)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazo-lin-5-ylacetyl]amino}-3-phenylpropanoate

Into a solution of methyl 3(R,S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoate (587 mg, 1.50 mmol) in 10% DCM/methanol (55 mL) was bubbled dry HCl gas for 2 hours. The mixture was stirred for 18 hours, then concentrated in vacuo. The crude imidate was dissolved in methanol (20 mL) and ammonium carbonate added. The resulting mixture was stirred for 18 hours, then filtered. The filtrate was concentrated in vacuo and the residue purified using flash chromatography (CHCl₃ --20% methanol/CHCl₃). Concentration of the appropriate fractions in vacuo followed by placing the residue under vacuum until constant weight afforded 193 mg (32%) of the desired amidines; CIMS (NH₃, e/z, relative abundance): 409 (M+H)⁺, 100%.

Part E: 3(R,S)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoic Acid, Trifluoroacetic Acid Salt

Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoate (45 mg, 0.113 mmol) was saponified using 0.5 M LiOH (0.6 mL, 0.3 mmol) according to Example 1, Part F, affording 28 mg (49%); CIMS (NH₃, e/z, relative abundance): 412 (M+H)⁺, 100%.

EXAMPLE 43A 5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoic Acid

Part A: Ethyl 3-(3-Butenoyl)aminopropionate

To an ice cold solution of vinylacetic acid (4.39 g, 51.0 mmol), ethyl 3-aminopropionate hydrochloride (8.49 g, 55.3 mmol) and TEA (7.8 mL, 56 mmol) in DCM (50 mL) was added DEC (10.54 g, 55.0 mmol). The resulting mixture was warmed to room temperature overnight (18 h). The mixture was then washed with water, 0.1 M HCl, sat. NaHCO₃, sat. NaCl and dried (MgSO₄). Concentration in vacuo followed by pumping until constant weight was achieved gave 6.34 g (67%) of the desired amide as a golden oil of purity suitable for further reaction; ¹ H NMR (300 MHz, CDCl₃) δ6.26 (bs, 1H), 5.98-5.85 (m, 1H), 5.25-5.17 (m, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.99 (dt, J=7.0, 1.1 Hz, 2H), 2.53 (t, J=5.9 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).

Part B: Ethyl 5(R,S)-N-[3-(4-Cyanophenyl)isoxazolin-5-ylacetyl]aminopropanoate

To a solution of ethyl 3-(3-butenoyl)aminopropionate (556 mg, 3.00 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 292 mg, 2.00 mmol) in CH₂ Cl₂ (7 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 4.2 mL, 2.8 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH₂ Cl₂. The combined organic was dried (MgSO4) and concentrated in vacuo. The crude product was then purified using flash chromatography (EtOAc), affording 386 mg (58%) of the desired isoxazoline; mp: 102.0-102.9° C.

Part C: Ethyl 5(R,S)-3-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoate

Into a solution of ethyl 5(R,S)-3-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]aminopropanoate (1.65 mg, 5.00 mmol) in 10% DCM/EtOH (165 mL) was bubbled HCl gas for 2 hours. After 18 hours, the solvent was evaporated in vacuo, the residue dissolved in EtOH (100 mL) and ammonium carbonate (14.41 g, 150 mmol) added. The resulting suspension was stirred at room temperature for 18 hours, then filtered and the resulting filtrate concentrated in vacuo. The residue was then crystallized from EtOH/ether, giving 713 mg (41%) of the desired amidine; ¹ H NMR (300 MHz, CD₃ OD) δ7.88 (AB quartet, Δ=16.8 Hz, J=8.4 Hz, 4H), 5.13 (m, 1H), 4.12 (q, J=7.3 Hz, 2H), 3.58 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 2H), 3.26 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.57 (m, 4H), 1.25 (t, J=7.3 Hz, 2H).

Part H: 5(R,S)-3-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoic Acid

To a solution of ethyl 5(R,S)-3-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoate (346 mg, 1.00 mmol) in EtOH (6 mL) was added 0.5 M LiOH. Upon mixing, a precipitate of the zwitterionic product began to form. After stirring for 18 hours at room temperature, the solid was collected by filtration, affording 365 mg of the title compound; ¹ H NMR (300 MHz, CD₃ OD) δ7.86 (AB quartet, Δ=18.3 Hz, J=8.4 Hz, 4H), 5.21 (m, 1H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.43 (m, 2H), 3.25 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.64 (dd, J=14.6, 6.8 Hz, 1H), 2.52 (m, 3H).

EXAMPLE 120a Methyl 3 (R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

Part A. Methyl (E)-5-phenyl-2-pentenoate

A solution of hydrocinnamaldehyde (13.42 g, 0.1 mol) and methyl(triphenylphosphoranylidene)acetate (33.44 g, 0.1 mol) in THF was stirred at reflux for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography using hexane:EtOAc::9:1. The desired product was obtained as a clear, pale yellow oil (8.0 g, 0.042 mol, 42%); ¹ H NMR (300 MHz, CDCl₃) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 7.1-6.9 (m, 1H), 5.85 (d, 1H, J=5.8 Hz), 3.75 (s, 3H), 2.8 (t, 2H, J=7.7 Hz), 2.55 (q, 2H, J=7.4 Hz); MS (NH₃ -DCI) 191 (M+H)⁺.

Part B. Methyl 3-(R)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate

A mixture of methyl (E)-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110° C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.18 g (0.0038 mol, 12%) of the desired product as a clear liquid; ¹ H NMR (300 MHz, CDCl₃) δ7.4-7.0 (m, 11H), 3.9 (q, 1H, J=6.5 Hz), 3.65 (s, 3H), 2.9-2.65 (m, 2H), 2.6-2.35 (m, 3H), 1.75-1.6 (m, 2H), 1.35 (d, 3H, J=6.2 Hz); MS (NH₃ -DCI) 312 (M+H)⁺.

Part C. Methyl 3-(R)-amino-5-phenylpentanoate  acetic acid salt

A mixture of methyl,3-(R)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate (0.72 g, 2.3 mmol), 20% Pd(OH)₂ /C (0.38 g), cyclohexene (8.2 mL), glacial HOAc (0.13 mL, 2.3 mmol), and MeOH (15 mL) was heated at reflux under N₂ for 20 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeCH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.46 g (96%) of a white solid, mp=73-75° C.; ¹ H NMR (300 MHz, DMSO) δ8.3 (bs, 2H), 7.35-7.15 (m, 5H), 3.65 (s, 3H), 3.45-3.35 (m, 1H), 2.8-2.6 (m, 4H), 2.0-1.7 (m, 2H); [α]_(D) ²⁵ --12.50° (c=0.0032, MeOH).

Part D. Methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (460 mg, 2.0 mmol) in EtOAc (15 ml) was added methyl 3-(R)-amino-5-phenylpentanoate acetic acid salt (410 mg, 2.0 mmol), TBTU (640 mg, 2.0 mmol), and Et₃ N (0.56 mL, 400 mg, 4.0 mmol). After stirring at room temp for 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 690 mg (83%) of a colorless oil. ¹ H NE (300 MHz, DMSO) δ 8.05 (brs, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.25 (m, 2H), 7.2-7.1 (m, 2H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6 (d, 3H, J=9.9 Hz), 3.3 (d, 2H, J=6.9 Hz), 3.25-3.15 (m, 1H), 2.75-2.35 (m, 6H), 1.8-1.6 (m, 2H); MS (NH₃ -DCI) 420 (M+H)⁺.

Part E Methyl 3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

This material was prepared from methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate (670 mg, 1.6 nmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 272 mg (39%) of a white solid of the title compound as a 1:1 mixture of diastereomers, mp=76-78° C.; ¹ H NMR (300 MHz, DMSO) δ 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.95-7.85 (m, 5H), 7.35-7.2 (m, 5H), 5.1-5.0 (m, 1H), 4.1-4.0 (m, 1H), 3.6 (s, 3H), 3.3-3.15 (m, 2H), 2.7-2.4 (m, 6H), 1.8-1.7 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH₃ -ESI,) 437 (M+H)⁺.

EXAMPLE 120b Methyl 3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

Part A. Methyl 3-(S)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate

A mixture of (E)-methyl-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110° C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.20 g (0.0039 mol, 13%) of the desired product as a clear liquid; ¹ H NMR (300 MHz, CDCl₃) δ 7.35-7.0 (m, 11H), 3.9 (q, 1H, J=6.6 Hz), 3.65 (s, 3H), 2.95-2.8 (m, 1H), 2.75-2.5 (m, 2H), 2.45-2.35 (m, 2H), 1.9-1.65 (m, 2H), 1.3 (d, 3H, J=6.6 Hz); MS (NH₃ -DCI) 312 (M+H)⁺.

Part B. Methyl 3-(S)-amino-5-phenylpentanoate  acetic acid salt

Methyl 3-(S)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate (0.93 g, 2.9 mmol), 20% Pd(OH)₂ /C (0.47 g), cyclohexene (10.1 mL), glacial HOAc (0.17 mL, 2.9 mmol), and MeOH (20 mL) were heated at reflux under N₂ for 48 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeOH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.65 g (80%) of a white solid, mp=86-88° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.35-7.15 (m, 5H), 5.3 (brs, 2H), 3.65 (s, 3H), 3.35-3.2 (m, 1H), 2.8-2.55 (m, 3H), 2.5-2.4 (m, 1H), 2.0 (s, 3H), 1.8 (q, 2H, J=7.4 Hz); [α]D²⁵ +9.55° (c=0.220, MeOH).

Part C. Methyl 3(S-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (700 mg, 2.6 mmol) in EtOAc (15 ml) was added methyl 3-(S)-amino-5-phenylpentanoate acetic acid salt (600 mg, 2.6 mmol), TBTU (830 mg, 2.6 mmol), and Et₃ N (1.09 mL, 790 mg, 7.8 mmol). After stirring at room temperature 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 420 mg (38%) of a colorless oil. ¹ H NMR (300 MHz, CDCl₃) δ 8.05-8.0 (m, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6-3.55 (m, 3H), 3.3-3.1 (m, 1H), 2.7-2.4 (m, 6H), 1.8-1.6 (m, 2H); MS (NH₃ -DCI) 420 (M+H)⁺.

Part D. Methyl 3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate

This material was prepared from methyl 3(S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate (360 mg, 0.86 mmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 230 mg (62%) of an amorphous solid of the title compound as a 1:1 mixture of diastereomers, mp=84-86° C.; ¹ H NMR (300 MHz, DMSO) δ 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.75-7.7 (m, 1H), 7.3-7.1 (m, 6H), 5.1-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.65 (s, 3H), 3.3-3.1 (m, 1H), 2.7-2.6 (m, 3H), 2.5-2.4 (m, 3H), 1.8-1.65 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH₃ -ESI) 437 (M+H)⁺.

EXAMPLE 189 5(R,S)-(2-Piperidin-4-yl)ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione

Part A. 3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal

To a suspension of PCC (11.52 g, 53.44 mmol) and sodium acetate (4.38 g, 53.4 mmol) in DCM (60 mL) was added a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanol (10.00 g, 41.09 mmol) in DCM (20 mL). After 4 hours at room temperature, the mixture was diluted with ether and passed though a short column of fluorisil® using ether as an eluent. The eluate was concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 8.32 g (84%) of the desired aldehyde as a colorless oil; ¹ H NMR (300 MHz, CDCl₃) δ 9.76 (t, J=1.5 Hz, 1H), 4.05 (bs, 2H), 2.64 (bt, J=11.7 Hz, 2H), 2.45 (dt, J=7.3, 1.5 Hz, 2H), 1.60 (m, 3H), 1.43 (s, 9H, overlapped with m, 2H), 1.08 (dq, J=12.1, 4.0 Hz, 2H).

Part B. (E,Z)-3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal Oxime

To a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal (3.905 g, 16.18 mmol) in EtOH : pyr=1:1 (20 mL) was added hydroxylamine hydrochloride (1.701 g, 24.48 mmol) and the resulting solution stirred at room temperature for 20 hours. Concentration in vacuo, resulted in an oil, which was dissolved in EtOAc and washed with 0.1 M HCl (3x), water, sat. CUSO₄ (2x), water and brine. The solution was dried over MgSO₄, concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 4.071 g (98%) of a 1:1 mixture of the (E,Z)-oxime as a colorless oil; ¹ H NMR (300 MHz, CDCl₃) δ 7.42 (t, J=6.2 Hz, 0.5H), 6.70 (t, J=5.5 Hz, 0.5H), 4.06 (bs, 2H), 2.67 (bt, J=12.8 Hz, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.66 (b, 2H), 1.45 (s, 9H, overlapped with m, 4H), 1.08 (m, 2H).

Part C. Methyl (5R,S)-3-{[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxymethylisoxazolin-5-yl}acetate

To a solution of (E,Z)-3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (503 mg, 1.96 mol) and dimethyl itaconate (620 mg, 3.92 mmol) in DCM (3 mL) was added a 5% solution of sodium hypochlorite (common household bleach, 3 mL, 2 mmol). The resulting mixture was stirred overnight (19 hours) at room temperature. The layers were separated and the aqueous washed with DCM (2x). The combined DCM fraction was dried over MgSO₄ and concentrated in vacuo. Purification using flash chromatography (hexanes--10% EtOAc/hexanes--50% EtOAc/hexanes) followed by concentration and pumping to constant weight afforded the desired isoxazoline (510 mg, 63%) as a colorless oil; ¹ H NMR (300 MHz, CDCl₃) δ 4.06 (bd, J=13.6 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.57 (d, J=17.6 Hz, 1H), 3.15 (d, J=16.5 Hz), 3.06 (d, J=17.6 Hz, 1H), 2.86 (d, J=16.5 Hz, 1H), 2.65 (bt, J=12.1 Hz, 2H), 2.36 (m, 2H), 1.65 (m, 2H, overlapped with H₂ O, 2H), 1.43 (s, 9H), 1.07 (m, 2H).

Part D. (5R,S)-3-{[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxyisoxazolin-5-yl}acetic Acid

To a solution of methyl (5R,S)-3-{[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxymethylisoxazolin-5-yl}acetate (380 mg, 0.921 mmol) was saponified using 0.5M LiOH (5 mL, 2.5 mmol) in THF (5 mL). The reaction was stirred at ambient temperature for 5 hours, according to Example 1, Part F to give 240 mg (68%) of the diacid; mp: 154.4-154.9° C.; ¹ H NMR (300 MHz, MeOH-d₄) δ 4.04 (bd, J=13.2 Hz, 2H), 3.52 (d, J=17.8 Hz, 1H), 3.18 (d, J=17.8 Hz, 1H), 2.97 (AB quartet, Δ=32.6, J=16.8 Hz, 2H), 2.72 (b, 2H), 2.39 (m, 2H), 1.71 (bd, J=13.2 Hz, 2H), 1.51 (m, 3H), 1.43 (s, 9H), 1.05 (m, 2H).

Part E. 5(R,S)-2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl-8-[(2-(1,1-dimethylethoxycarbonyl)ethyl]-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione

To a solution of (5R,S)-3-{[2-(N-t-butyloxycarbon-ylpiperidin-4-yl)ethyl]-5-carboxyisoxazolin-5-yl}acetic acid (700 mg, 1.82 mmol) in THF (5 mL) was added DCC (378 mg, 1.83 mmol), and the resulting suspension was stirred for 30 min at room temperature. To this mixture was added a suspension of β-alanine t-butyl ester hydrochloride (372 mg, 2.05 mmol) and TEA (300 μL, 2.15 mmol) in THF (5 mL). The mixture was stirred overnight (18 hours) at room temperature. Following dilution with EtOAc, the mixture was filtered and the filtrate washed with 0.1M HCl, sat. NaHCO₃ and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (46%) of the crude amide. A portion of this material (420 mg, 0.821 mmol) was dissolved in THF (4 mL). To this solution was added HOSuc (100 mg, 0.869 mmol) followed by DCC (180 mg, 0.872 mmol). The resulting suspension was stirred at room temperature for 18 hours. Following dilution with ether, the mixture was cooled to 0° C. and filtered. The filtrate was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (86%) of the crude active ester. A portion of this material (402 mg, 0.660 mmol) was dissolved in DMF (5 mL) at 0° C. To this solution was added NaH (16 mg, 0.66 mmol). After 3 hours at 0° C., the reaction was quenched with HOAc. After dilution with EtOAc, the mixture was washed with water (4x), sat. NaHCO₃, water, 0.1M HCl and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 230 mg (70%) of the crude imide. The crude material was purified using flash chromatography (CHCl₃ --5% MeOH/CHCl₃), affording 149 mg (46%) of a colorless oil after concentration of the appropriate fractions and pumping to constant weight; ¹ H NMR (300 MHz, CDCl₃) δ 4.09 (b, 2H) , 3.82 (t, J=7.3 Hz, 2H), 3.54 (d, J=17.2 Hz, 1H), 3.12 (d, J=18.7 Hz, 1H), 2.98 (d, J=17.2 Hz, 1H), 2.83 (d, J=18.7 Hz, 1H), 2.69 (m, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.42 (m, 2H), 1.68 (m, 2H), 1.57 (m, 2H), 1.45 (s, 9H, coincident with m, 1H), 1.11 (m, 2H).

Part F. 5(R,S)-(2-Piperidin-4-yl)ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione

To a solution of 5(R,S)-2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl-8-[(2-(1,1-dimethylethoxycarbonyl)ethyl]-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione (75 mg, 0.152 mmol) in DCM (1 mL) was added TFA (0.5 mL, 8 mmol). The reaction was stirred at room temperature for 2 hours, then was concentrated in vacuo. Excess TFA was chased by rotary evaporation with toluene (2x). Crystallization from MeOH/ether gave 10 mg (15%) of the desired amino acid after pumping to constant weight; mp: 178.0-179.1° C.; ¹ H NMR (400 MHz, DMSO-d₆, 60° C.) δ 12.15 (bs, 1H). 8.26 (bs, 2H), 3.64 (m, 2H), 3.39 (d, J=17.8 Hz, 1H), 3.26 (m, 3H), 2.98 (AB quartet, Δ=71.3 Hz, J=18.3 Hz, 2H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d₅), 2.37 (t, J=7.6 Hz, 2H), 1.84 (bd, J=11.7 Hz, 2H), 1.58 (m, 1H), 1.52 (t, J=7.6 Hz, 2H), 1.29 (m, 2H).

EXAMPLE 275 N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic Acid TFA Salt

Part A. 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid.

To a solution of 4-cyanobenzaldoxime (see Ex 43, Part A) (312 g, 2.13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyl acetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 ml) was added in a dropwise fashion over 2h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 ml ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 ml ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 ml ether. The organic phase was washed three times with 150 ml water, once with brine, dried (MgSO₄) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material. Anal. Calcd for C₁₂ H₁₀ N₂ O₃ : C,62.61; H,4.38; N, 12.17. Found: C. 62.37; H 4.47; N, 11.71. ¹ H NMR(300 MHz, CDCl₃): δ 7.77-7.76 (d, 2H, J=1.8 Hz); 7.72-7.71 (d, 2H, J=1.8 Hz); 5.22-5.14 (m, 1H); 3.63-3.54 (dd, 1H, J=10.6 Hz, 16.8 Hz); 3.19-3.11 (dd, 1H, J=7.3Hz, 16.8 Hz); 3.00-2.93 (dd, 1H, J=6.2 Hz, 16.5 Hz); 2.79-2.72 (dd, 1H, J=7.3 Hz, 16.5 Hz). IR(KBr pellet): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm⁻¹.

Part B. Methyl N² -Cbz-L-2,3-diaminopropionate HCl salt.

N² -Cbz-L-2,3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in 20 mL methanol and 20 mL 4 N HCl in dioxane and the solution was stirred for 4 hours and then concentrated to give a solid. The solid was washed with ether several times to give 2.50 g (87%) product. NMR (DMSO-d₆): δ 8.38 (b, 3H); 7.96 (d, 1H); 7.38 (m, 5H); 5.05 (s, 2H); 4.44 (m, 1H); 3.66 (s, 3H); 3.14 (m, 2H).

Part C. Methyl N² -Cbz-N³ -[3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate.

To a solution of 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid. (19 mmol, 4.37 g), methyl N² -Cbz-L-2,3-diaminopropionate HCl salt (20 mmol, 5.76 g) and triethylamine (60 mmol, 8.36 mL) was added TBTU (20 mmol, 6.42 g) and the solution was stirred for 2 hours. Ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated. Crystallization from ethyl acetate/ether gave 6.85 g (78%) product. NMR (DMSO-d₆): δ 8.16 (t, 1H); 7.92 (d, 2H); 7.82 (d, 2H); 7.68 (d, 1H); 7.36 (m, 5H); 5.04 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H).

Part D. Methyl N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate HCl salt.

HCl gas was bubbled into a solution of methyl N² -Cbz-N³ -[3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate (2.1 mmol, 1.0 g) for 1 hour and the solution was stirred overnight and concentrated. The residue was dissolved in 30 mL 2 M ammonia in methanol and the solution was stirred overnight. and concentrated to give 1.2 g crude product.

Part E. N³ -[3- (4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt.

Methyl N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate HCl salt (200 mg) was saponified with 1 mL methanol and 1 mL 1 N NaOH for 1 hour and acidified with acetic acid. Purification on reversed phase HPLC gave 40 mg product. ESI (M+H)⁺ : Calcd 334.2; Found 334.2.

EXAMPLE 276 N² -Cbz-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt

Part A. Methyl N² -Cbz-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt.

To a solution of the compound of Ex. 275, part D (1.0 mmol, 385 mg) and sodium bicarbonate (5.0 mmol, 400 g) in 2 mL water, 2 mL acetonitrile and 1 mL DMF was added benzyl chloroformate (1 mmol, 143 μL) and the mixture was stirred for 2 hours at room temperature. The solution was filtered, acidified with TFA and purified on reversed phase HPLC to give 150 mg (25%) product. NMR (DMSO-d₆): δ 9.40 (s, 2H); 9.20 (s, 2H); 8.18 (t, 1H); 7.86 (m, 4H); 7.68 (d, 1H); 7.35 (m, 5H); 5.02 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.52 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H).

Part B. N² -Cbz-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt

Methyl N² -Cbz-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt (0.12 mmol, 70 mg) was dissolved in 2 mL methanol and 1 mL 1 N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 50 mg (74%) product. ESI (M+H)⁺ : Calcd 468.2; Found 468.2.

EXAMPLE 278 N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt

Part A. Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt.

To a solution of the compound of Ex. 275, part E (1.0 mmol, 385 mg) and sodium bicarbonate (2.5 mmol, 200 mg) in 2 mL water, 2 mL acetonitrile and 1 mL DMF cooled in an ice bath was added n-butyl chloroformate (1 mmol, 127 μL). After stirring for 1 hour, the solution was acidified with acetic acid and purified on reversed phase HPLC to give 150 mg (27%) product. NMR (DMSO-d₆): δ 9.40 (s, 2H); 9.20 (s, 2H); 8.16 (t, 1H); 7.86 (m, 4H); 7.47 (d, 1H); 5.02 (m, 1H); 4.16 (m, 1H); 3.94 (t, 2H); 3.62 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H). ESI (M+H)⁺ : Calcd 448.3; Found 448.3.

Part B. N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-(S)-2,3-diaminopropionic acid TFA salt.

Methyl N2-n-butyloxycarbonyl-N3-[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt (0.107 mmol, 60 mg) was dissolved in 2 mL methanol and 2 mL 1 N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 53 mg (89%) product. ESI (M+H)⁺ : Calcd 434.3; Found 434.3.

EXAMPLE 278a Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Mesylate salt.

Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (500 mg, 1.03 mmol) was dissolved in 20 mL methanol and methanesulfonic acid (0.335 mL, 5 mmol) was added. The solution was allowed to stand at room temperature overnight and the solvent was removed by concentration. The residue was taken up in 20 mL methanol and the solution was allowed to stand at room temperature overnight. The solvent was removed by concentration and the residue was triturated with 8 mL 2-propanol. The solid product was isolated by filtration and dissolved in 12 mL 2-propanol by warming. After cooling to room temperature, crystalline solid formed. The mixture was allowed to stand in a refrigerator overnight. The crystal was filtered, washed with cold 2-propanol and dried. Yield 230 mg (41%). ES-MS (M+1): calcd 448.3; found 448.3. Analysis for C₂₂ H₃₃ N₅ O₉ S: calcd C 48.61, H 6.13, N 12.88; found C 48.38, H 5.91, N12.65.

EXAMPLE 278b N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic acid TFA salt.

To a solution of methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate hydrochloride salt (600 mg, 1.24 mmol) in 20 mL MeOH and 20 mL water cooled in an ice bath was added 1 N LiOH (1.3 mL, 1.3 mmol) over 5 min and the solution was stirred at room temperature for 5 hours. The solvents were removed by concentration at 25° C. The residue was taken up in 3 mL water, 3 mL acetonitrile, and 0.2 mL TFA. Purification by reversed phase HPLC gave 610 mg (89%) product. ES-MS (M+1): calcd 434.3; found 434.3.

EXAMPLE 298 N² -n-Butanesulfonyl-N³ -[3-(4-amidino-phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 454 (M+H)⁺, (100%).

EXAMPLE 299 N² -Phenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 474 (M+H)⁺, (100%).

EXAMPLE 314A Methyl N² -n-butyloxycarbonl-N³ -[3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt

Part A: Methyl N² -Cbz-N³ -Boc-L-2,3-diaminopropionate.

To a solution of methyl N² -Cbz-(S)-2,3-diaminopropionate HCl salt (16.3 mmol, 4.7 g) and ditert-butyl dicarbonate (16.3 mmol, 3.56 g) in 30 mL chloroform cooled in an ice bath was added triethylamine (34 mmol, 4.7 mL) and the solution was stirred in the ice bath for 1 hour and at room temperature for 3 hours and concentrated. The residue was taken up in ethyl acetate and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR (DMSO-d₆): δ 7.60 (d, 1H); 7.35 (m, 5H); 6.88 (t, 1H); 5.02 (s, 2H); 4.14 (m, 1H); 3.60 (s, 3H); 3.28 (m, 2H); 1.37 (s, 9H).

Part B: Methyl N³ -Boc-(S)-2,3-diaminopropionate Formic acid salt.

A mixture of methyl N² -Cbz-N³ -Boc-(S)-2,3-diaminopropionate. (14 mmo, 5.0 g), formic acid (42 mmol, 1.6 mL) and 10% Pd/C (500 mg) in 40 mL methanol was stirred at room temperature for 1 hour and filtered through a celite. The filtrate was concentrated and the residue was triturated with ether-petroleum ether to give 3.7 g (100%) solid product. NMR (DMSO-d₆): δ8.20(s, 1H); 6.90 (t, 1H); 5.36 (b, 3H); 3.61 9s, 3H); 3.51 (t, 1H); 3.18 (t, 2H); 1.38 (s, 9H).

Part C: Methyl N² -n-butyloxycarbonyl-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N₃ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt (14 mmol, 3.7 g) and NaHCO₃ (40 mmol, 3.4 g) in 10 mL water and 10 mL THF cooled in an ice bath was added slowly butyl chloroformate (16 mmol, 2 mL) over 15 min. After stirring for 1 hour, ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated to give 4.4 g (100%) oily product. NMR (DMSO-d₆): δ 7.37 (d, 1H); 6.84 (t, 1H); 4.10 (m, 1H); 3.96 (t, 2H); 3.60 (s, 3H); 3.26 (m, 2H); 1.52 (m, 2H); 1.38 (s, 9H); 1.36 (m, 2H); 0.88 (t, 3H).

Part D: Methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt.

Methyl N² -n-butyloxycarbonyl-N³ -Boc-(S)-2,3-diaminopropionate (13.9 mmol, 4.4 g) was dissolved in 25 mL methylene chloride and 35 mL TFA and after 1 hour, the solution was concentrated to give an oily product. Yield 4.8 g (100%). NMR (DMSO-d₆): δ 8.02 (b, 3H); 7.68 (d, 2H); 4.38 (m, 1H); 3.99 (t, 2H); 3.68 (s, 3H); 3.22 (m, 1H); 3.06 (m, 1H); 1.55 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H).

Part E: Methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate

To a solution of 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid (5.2 mmol, 1.2 g) [Chiral starting material was prepared from the racemic compound of Ex. 275, Part A by resolution on a 50 X 2 cm Chiralpak AD column using 0.1% TFA/EtOH at 10° C. to give S-isomer (faster eluting) and R-isomer (slower eluting). Alternately, the isomers were resolved by crystallization of the chinconidine salt of the 5-S isomer of the isoxazolines from acetone, leaving the 5(R),isomer in the mother liquor. The absolute stereochemistry of the crystalline salt was determined by X-ray crystallography to be the 5(S) isoxazoline.] and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt (6 mmol, 1.53 g) in 20 ml DMF cooled in an ice bath was added diisopropylethylamine (20 mmol, 3.5 mL) followed by BOP (5.5 mmol, 2.43 g). After stirring at room temperature for 3 hours, ethyl acetate was added and the solution was washed with 0.5 N HCl, brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give 1.9 g (87%) product. NMR (DMSO-d₆): δ 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).

Part F: Methyl-N² -n-butyloxycarbonyl-N³ [3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt.

To a solution of methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate (4.4 mmol, 1.9 g) in 50 mL methanol was bubbled with HCl gas at 0° C. for 1 hour and the solution was stirred at room temperature for 5 hours and concentrated. The residue was taken up in 20 mL methanol and ammonium carbonate (11 mmol, 1.1 g) was added. The mixture was stirred at room temperature overnight and concentrated. The solid was dissolved in ethanol/water/TFA and purification on reversed phase HPLC gave 1.0 g (40%) product. ESI (M+H)⁺ : Calcd 448.3; Found 448.3.

EXAMPLE 314B Methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt

Part A: 3-(4-cyanophenyl)-5(R)-ylacetic acid

This material was resolved from 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic acid as described above in the proceudure for Example 314A, Part E.

Part B: Methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate.

This material was synthesized from 3-(4-cyanophenyl)-5(R)-ylacetic acid (4.3 mmol, 1.0 g), Methyl N² -butyloxycarbonyl-(S)-2,3-diaitinopropionate TFA salt (5 mmol, 1.27 g), BOP (4.5 mmol, 2 g) and diisopropylethylamine (16 mmol, 2.8 mL) using the same procedure as for XVI. Yield 1.75 g (95%). NMR (DMSO-d₆): δ 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).

Part C: Methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt

This compound was synthesized from Methyl-N² -n-butyloxycarbonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (4.0 mmol, 1.7 g) using the same procedure as for Example 314A, Part G. Yield 1.0 g (45%). ESI (M+H)⁺ : Calcd 448.3; Found 448.3.

EXAMPLE 317 N² -(2-Phenylethylsulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 502 (M+H)⁺, (100%).

EXAMPLE 344 Methyl 3(R)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoate

Part A. (E)-Methyl 2-heptenoate

To a solution of diethyl methylphosphonoacetate (19 ml, 104 mmol) in dry THF (800 ml) at -4° C. was added 64 ml of n-BuLi (1.6 M in hexane, 102 mmol) dropwise over 45 min. The resulting solution was stirred 1 h at room temp. Valeraldehyle (10.0 ml, 94 mmol) was added and stirred 3.5 h at room temp. The reaction was quenched with 25 ml sat. NH₄ Cl. Solvents were distilled at atmospheric pressure, and the resulting solids were taken up in EtOAc, extracted with water and brine, and dried with Na₂ SO₄. The solvents were again distilled at atmospheric pressure, and the resulting yellow liquid was distilled under house vacuum to yield 7.2 g clear liquid, boiling range under house vacuum 90-125° C.; HRMS, e/z Calc. for (M+H)⁺ : 143.1072. Found: 143.1070; IR(film) 1728, 1658 cm⁻¹.

Part B. N-(1-(R)-1-Phenylethyl)benzamide

A solution of benzoyl chloride (22.5 mL, 0.19 mole) in dichloromethane (10 mL) was added dropwise over 1.5 h to a 0° C. solution of (R)-(+)-α-methylbenzylamine (25 mL, 0.19 mole), triethylamine (31 mL, 0.22 mole), and 4-DMAP (100 mg), in dichloromethane (1 L). After 1.75 h at 0° C. the mixture was concentrated in vacuo, then diluted with EtOAc. This mixture was extracted with water, 1 M HCl, water, and brine, then dried (MgSO₄) and concentrated to yield 43.4 g of a colorless crystalline solid; mp 121.0-121.5° C.; IR(KBr) 3332, 1636 cm⁻¹ ; [α]_(D) ²⁵ -2.30° (c=1.002, CH₂ Cl₂); Anal. Calc. for C₁₅ H₁₅ NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.88; H, 6.65; N, 6.17.

Part C. N-(1-(R)-1-Phenylethyl)-N-benzylamine

BH₃ /THF (1 M in THF, 220 mL, 220 mmol) was added dropwise over 1 h to a 0° C. solution of the above benzamide (20 g, 89 mmol) in dry THF (200 mL). The ice bath was removed, and the mixture was heated to reflux for 40 h. A TLC analysis indicated incomplete reaction, so more BH₃ /THF (1 M in THF, 30 mL, 30 mmol) was added, and heating resumed for 22.5 h. After cooling, MeOH (250 mL) was added dropwise cautiously over 5 h. The resulting mixture was boiled for 2 h, then cooled and concentrated in vacuo. Reconcentration from MeOH (2×500 mL) and drying under high vacuum gave 19.3 g of an oil containing a small amount of a precipitate. This crude product was stirred with hot 2 M HCl (140 mL) to generate a clear solution, then slowly cooled to RT, and ultimately in an ice bath to yield a crystalline solid, as described by Simpkins (Tetrahedron 1990, 46(2), 523). The solid was collected by filtration and rinsed with a small amount of water. After air drying for 3 d, 16.35 g of the hydrochloride salt was obtained; mp 178.5-179.5° C.; [α]_(D) ²¹ +18.9° (c=4.0, EtOH). The salt was converted to the free base by extraction with Et₂ O and aq. KOH, then Kugelrohr distilled, oven temp. 120-140° C. (1.1 mm Hg) to give 12.5 g of an oil; [α]_(D) ²¹ +61.2° (c=3.98, EtOH); Anal. Calc. for C₁₅ H₁₇ N: C, 85.26; H, 8.11; N, 6.63. Found: C, 84.93; H, 7.75; N, 6.58.

Part D. Methyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate

Following the asymmetric Michael addition method of Davies (Tetrahedron:Asymmetry 1991, 2(3), 183), n-butyllithium (1.6 M in hexanes, 4.4 mL, 7.0 mmol) was added dropwise over 3 min to a 0° C. solution of N-(1-(R)-1-phenylethyl)-N-benzylamine (1.5 g, 7.0 mmol) in dry THF (35 mL). After 30 min, the resulting dark pinkish-red solution was cooled to -78° C., and a solution of methyl 2-heptenoate (0.50 g, 3.5 mmol) in THF (10 mL) was added dropwise over 10 min. After 13 min, the cold reaction was quenched with saturated NH₄ Cl (7 mL). After warming to RT, the mixture was extracted with Et₂ O and brine, dried (MgSO4), and concentrated in vacuo. The product was purified by chromatography over silica gel, eluting with 0% to 50% EtOAc in hexane. The cleanest major product fractions (apart from a few mixed fractions) were concentrated in vacuo to give 0.91 g of a pale yellow oil which by NMR is a single diastereomer, with the newly generated asymmetric center assigned as 3(R) by analogy with the Davies reference above; ¹³ C NMR (300 MHz, CDCl₃) δ 173.31, 143.40, 141.78, 128.40, 128.27, 128.11, 128.00, 126.91, 126.67, 57.90, 54.22, 51.32, 50.05, 36.83, 33.28, 29.32, 22.72, 19.40, 14.12; [α]_(D) ²⁵ +12.96° (c=0.602, MeOH).

Part E. Methyl 3-(R)-aminoheptanoate  acetic acid salt

Methyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate (0.70 g, 2.0 mmol), 20% Pd(OH)₂ /C (0.35 g), cyclohexene (7 mL), glacial HOAc (0.12 mL, 2.1 mmol), and MeOH (14 mL) were heated at reflux under N₂ for 20.5 h. After cooling, the catalyst was removed by filtration thru a Celite plug, rinsed with MeOH, and the solution concentrated in vacuo. Drying overnight under high vacuum yielded 0.43 g of a viscous oil; ¹³ C NMR (300 MHz, CDCl₃) δ 177.64, 171.52, 51.97, 48.22, 37.24, 33.08, 27.50, 23.31, 22.29, 13.76; [α]_(D) ²⁵ -10.6° (c=0.602, MeOH).

Part F. Methyl 3(R)-[5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}heptanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (300 mg, 1.3 mmol) in EtOAc (10 ml) was added methyl 3-(R)-aminoheptanoate acetic acid salt (287 mg, 1.3 mmol), TBTU (420 mg, 1.3 mmol), and Et3N (600 μl, 4.3 mmol). After stirring at room temp 2.5 h, the reaction mixture was extracted with 5% KHSO₄, sat NaHCO₃, and brine, then dried with Na₂ SO₄. Evaporation, followed by chromatography over silica gel in 50-100% EtOAc/hexanes yielded 245 mg colorless glass. MS (NH₃ -DCI) Calc. for (M+H)⁺ : 372, (M+NH₄)⁺ : 389. Found: 372, 389.

Part G. Methyl 3(R)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoate

To a solution of methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}heptanoate (179 mg, 0.48 mmol) in 15 ml dry MeOH at 0° C., was added a stream of HCl gas generated from dropping two 20 ml portions of H₂ SO₄ into solid NaCl over 35 min. After stirring 20 h at room temp, the solvent was removed with a rapid stream of N₂. Et₂ O was added and removed with a rapid stream of N₂. The resulting gummy oil was taken up in 15 ml dry MeOH, to which was added (NH₄)₂ CO₃ (1.1 g, 11.4 mmol). After stirring 19.5 h at room temp, the solvent was removed with a rapid stream of N₂, and the resulting white solid was purified by chromatography over silica gel, eluting with 0-20% MeOH/CHCl₃. Purified product was taken up in 5% MeOH/CHCl₃ and filtered. Concentration of the filtrate yielded 100 mg white solid. IR(KBr) 3600-2800, 1734, 1676, 1640 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 389.2189. Found: 389.2192.

EXAMPLE 348 Ethyl 3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-5-methylhexanoate  trifluoroacetic Acid Salt

Part A. (E)-Ethyl 5-methyl-2-hexenoate

Prepared in analogous fashion to rethyl 2-heptenoate, using triethyl phosphonoacetate, stirring 17 h at room temp upon addition of isovaleraldehyde. Distillation under house vacuum yielded 72% clear oil, boiling range under house vacuum 80-130° C.; IR(film) 1724, 1656 cm⁻¹.

Part B. Ethyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]-5-methylhexanoate

Prepared in analogous fashion via the asymmetric Michael addition of Ex. 344, part D above. Yield a viscous pale yellow oil (65%); ¹³ C NMR (300 MHz, CDCl₃) δ 172.83, 143.56, 142.17, 128.27, 128.21, 128.15, 128.03, 126.96, 126.60, 60.10, 58.56, 52.43, 50.09, 3.23, 36.72, 24.76, 23.48, 22.13, 20.20, 14.21; [α]_(D) ²⁵ +5.12° (c=0.606, EtOH).

Part C. Ethyl 3-(R)-amino-5-methylhexanoate  acetic acid salt

Prepared as previously described except EtOH was used as solvent. Yield a waxy solid (94%); mp 57-61° C.; HRMS, e/z Calc. for (M+H)⁺ : 174.1494. Found: 174.1485.

Part D. Ethyl 3-(R)-amino-5-methylhexanoate  hydrochloric acid salt

The above acetic acid salt (1.1 g, 4.7 mmol) was stirred 4 min in 4 M HCl/dioxane (5.0 ml). The resulting solution was triturated with Et₂ O, cooled, and the clear liquid decanted, leaving an orange oil which solidified to 960 mg waxy solid on high vacuum; ¹ H NMR (300 MHz, CDCl₃) ∂ 8.49 (br, 3H), 4.20 (q, J=7.3, 2H), 3.70-3.65 (m, 1H), 2.86-2.80 (m, 2H), 1.83-1.80 (m, 2H), 1.58-1.54 (m, 1H), 1.30-1.26 (t, J=7.3, 3H), 0.99-0.91 (m, 6H).

Part E. Ethyl 3(R)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-5-methylhexanoate

To a suspension of 3-(4-(N-t-butoxycarbonylamidino)phenyl]isoxazolin-5-ylacetic acid (78 mg, 0.22 mmol) in EtOAc (5 ml) was added ethyl 3-(R)-amino-5-methylhexanoate hydrochloride salt (47 mg, 0.22 mmol), TBTU (72 mg, 0.22 mmol), and Et₃ N (100 μl, 0.72 mmol). After stirring 6 h at room temp, the reaction mixture was extracted with pH 4 buffer (potassium hydrogen phthalate), sat NaHCO₃, and brine, then dried with Na₂ SO₄. Evaporation, followed by chromatography over silica gel in 100% EtOAc yielded 33 mg colorless glass; ¹ H NMR (300 MHz, CDCl₃) ∂ 7.90 (d, J=8.4, 2H), 7.70 (dd, J=8.5, J'=1.9, 2H), 6.32-6.28 (m, 1H), 5.13-5.11 (m, 1H), 4.34-4.33 (m, 1H), 4.17-4.09 (m, 2H), 3.56-3.47 (m, 1H), 3.25-3.17 (m, 1H), 2.71-2.46 (m, 4H), 1.66-1.47 (m, 2H), 1.56 (s, 9H), 1.31-1.23 (m, 4H), 0.92 (dd, J=6.6, J'=1.8, 3H), 0.84 (d, J=6.6, 3H).

Part F. Ethyl 3(R)-{5(R,S) -N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-5-methyl hexanoate  trifluoroacetic acid salt

The product from Part E above (29 mg, 0.058 mmol) was dissolved in DCM (300 μl), to which was added TFA (100 μl). The resulting solution was stirred at room temp under a CaSO₄ drying tube for 3.5 h, and triturated with Et₂ O. 24 mg white solid were collected by filtration; ¹ H NMR (300 MHz, CDCl₃) ∂ 9.4 (br, 1H), 9.0 (br, 1H), 7.8 (s, 4H), 5.0 (m, 1H), 4.2 (m, 1H), 4.0 (q, 2H), 3.6 (m, 1H), 3.3 (m, 2H), 2.4 (m, 3H), 1.6 (m, 1H), 1.4 (m, 1H), 1.2 (m, 4H), 0.8 (m, 6H); HRMS, e/z Calc. for (M+H)⁺ : 403.2345. Found: 403.2363.

EXAMPLE 350 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate  hydrochloric acid salt;

Part A. Methyl phenylthioacetoacetate

To a solution of thiophenol (5.00 ml, 48.6 mmol) in DMF (20 ml), K₂ CO₃ (10.09 g, 73 mmol) and methyl chloroacetoacetate (5.93 ml, 48.6 mmol) were added. The reaction mixture was stirred 6 h at 50° C., diluted with EtOAc, and extracted with saturated Na₂ SO₄, water, and brine, then dried (Na₂ SO₄) and concentrated. The resulting oil was chromatographed with 20% EtOAc in Hexane to yield 9.40 g yellow oil; MS (CH4-DCI) Calc. for (M+H)⁺ : 224. Found: 224; IR(KBr) 2954, 1656, 1438, 626 cm⁻¹.

Part B. Methyl-3(R,S)-amino-4-penylthiobutanoate

To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1 M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na₂ SO₄ and concentrated to yield 0.61 g yellow oil; MS (NH3-CI/DDIP) Calc. for (M+H)⁺ : 226. Found: 226; ¹ H NMR (300 MHz, CDCl₃) δ 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).

Part C. Methyl-3(R,S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (0.50 g, 2 mmol) in EtOAc (10 ml), methyl-3(R,S)amino-4-(phenylthio)butanoate (0.51 g, 2 mmol), TBTU (0.71 g, 2 mmol), and Et₃ N (1.24 ml, 8.9 mmol) were added. The reaction mixture was stirred 2 h at room temperature, diluted with EtOAc, washed with 5% citric acid, saturated NaHCO₃, and brine, dried over Na₂ SO₄, concentrated, and the resulting oil was chromatographed over silica gel in 100% EtOAc to yield 0.61 g of a yellow glass: MS (NH₃ -CI/DDIP) Calc. for (M+H)⁺ : 438.1. Found: 438.1; Anal. Calc. for C₃₂ H₂₃ N₃ O₄ S₁ : C, 63.31; H, 5.30; N, 9.60; S, 7.33. Found: C, 62.99; H, 5.22; N, 9.53; S, 7.30.

Part D. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate  hydrochloric acid salt

The product from Part C above (0.30 g,0.68 mmol) was dissolved in dry MeOH (20 ml) at 0° C. To the resulting solution, HCl gas was bubbled in from a generator as described in Example 344, Part G, over a period of 2 h. The generator was removed and the reaction mixture stirred at 0° C. for 18 h, then concentrated and triturated with CHCl₃. The resulting precipitate was collected by filtration and redissolved in dry MeOH (20 ml). To this solution, ammonium carbonate (0.99 g, 10 mmol) was added and the mixture stirred at room temperature for 18 h. The solution was concentrated and recrystallized from DCM/MeOH to yield 0.14 g white solid; HRMS, e/z Calc. for (M+H)⁺ : 455.1753. Found: 455.175; ¹ H NMR (300 MHz, d₆ -DMSO) δ 9.44 (br s, 1H), 9.18 (br s, 1H), 8.22 (d, J=10, 1H), 7.86 (m, 4H), 7.41-7.25 (m, 4H), 7.2 (m, 1H), 5.03 (m, 1H), 4.2 (m, 1H), 3.59 (s, 3H), 3.29-3.05 (m, 4H), 2.8-2.39 (m, 4H).

EXAMPLE 359 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoate  Trifluoroacetic Acid Salt;

Part A. Methyl 3-(R,S)-hydroxy-4-aminobutanoate  hydrochloric acid salt

Chlorotrimethylsilane (100 mL, 0.79 mol) was added dropwise over 1.5 h to a stirred 0° C. suspension of 4-amino-3-(R,S)-hydroxybutyric acid (25 g, 0.21 mol) in MeOH (1 L). The resulting clear solution was allowed to slowly warm to room temperature overnight. The solvent was evaporated in vacuo, and the resulting residue was reconcentrated from more MeOH (2×500 mL). Drying under high vacuum produced 37 g of a-viscous oil; ¹³ C NMR (300 MHz, d₆ -DMSO) δ 171.42, 90.14, 64.67, 51.89, 44.39; Anal. Calc. for C₅ H_(l6) ClNO₃ : C, 35.41; H, 7.13; N, 8.26; Cl, 20.90. Found: C, 35.18; H, 7.09; N, 8.18; Cl, 20.77.

Part B. Methyl 3-(R,S)-hydroxy-4-(phenylsulfonamido)butanoate

A solution of benzenesulfonyl chloride (7.5 mL, 59 mmol) in dichloromethane (10 mL) was added dropwise over 55 min to a 0° C. solution of the Part A amine salt (10 g, 50 mmol), and Et₃ N (17 mL, 120 mol) in dichloromethane (110 mL). The mixture was allowed to slowly warm to room temperature, and stirring was continued over the weekend. After solvent removal in vacuo, the mixture was diluted with EtOAc and extracted with H₂ O, 0.1 M HCl, and brine. Drying (MgSO₄) and solvent removal in vacuo yielded 14.6 g of a viscous oil; ¹³ C NMR (300 MHz, CDCl₃) δ 172.67, 139.79, 132.78, 129.22, 127.02, 66.77, 52.01, 47.72, 38.31; Anal. Calc. for C₁₁ H₁₅ NO₅ S: C, 48.34; H, 5.53; N, 5.13; S, 11.73. Found: C, 48.44; H, 5.61; N, 4.90; S, 11.34.

Part C. Methyl 3-oxo-4-(phenylsulfonamido)butanoate

The Part B alcohol (2.8 g, 10 mmol) was oxidized with Jones reagent under standard conditions. The ketone was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, to yield 1.11 g of a waxy solid; mp 94.5-95.5° C.; ¹³ C NMR (300 MHz, CDCl₃) δ 197.08, 166.80, 139.17, 133.08, 129.29, 127.17, 52.71, 51.91, 46.15; Anal. Calc. for C₁₁ H₁₃ NO₅ S: C, 48.70; H, 4.83; N, 5.16; S, 11.82. Found: C, 48.77; H, 4.69; N, 5.08; S, 11.88.

Part D. Methyl 3-(R,S)-3-amino-4-(phenylsulfonamido)butanoate

To a room temperature solution of the Part C ketone (0.71 g, 2.6 mmol) in MeOH (7 mL) and THF (3 mL) was added ammonium formate (2.5 g, 39 mmol) and sodium cyanoborohydride (0.25 g, 3.9 mmol). After 45.5 h, solvent was evaporated, and the residue was diluted with EtOAc (70 mL). This solution was extracted with 1.0 M NaOH, H₂ O, and brine. After concentration, the product was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, then 1% to 20% MeOH in EtOAc to yield 0.16 g of a viscous oil, which eventually solidified; ¹ H NMR (300 MHz, CDCl₃) ∂ 9.79 (br, 2H), 7.84 (d, 2H, J=8 Hz), 7.81 (br, 1H), 7.68-7.53 (m, 3H), 4.05-3.92 (m, 1H), 3.75 (s, 3H), 3.33-3.17 (m, 2H), 2.89-2.72 (m, 2H); HRMS, e/z Calc. for (M+H)⁺ : 273.0909. Found: 273.0916.

Part E. Methyl 3-(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoate

This compound was prepared analogous to Example 348, Part E, stirring 24 h in 5 ml EtOAc and 1 ml DMF. Chromatography in 5% MeOH/CHCl₃ yielded 80% of an orange solid; IR(KBr) 3296, 2338, 1736, 1660, 1618 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 602.2285. Found: 602.2270.

Part F. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoae  trifluoroacetic acid salt

The product from Part E was deprotected analogously to Example 348, Part F, yielding 86% pink solid; IR(KBr) 3312, 3104, 1734, 1670; HRMS, e/z Calc. for (M+H)⁺ : 502.1760. Found: 502.1761. The more active diastereomer (based on PRP assay) was isolated from the above mixture by SFC HPLC, Chiralpak AD--2×25 cm, eluted with 0.1% TFA/25% MeOH/75% CO₂. Under these conditions, the more active diastereomer eluted last.

EXAMPLE 362 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonamido)butanoate  trifluoroacetic acid salt;

Part A. Methyl 3-(R,S)-hydroxy-4-(n-butylsulfonamido)butanoate

This compound was prepared entirely analogously to Ex.359, Part B, using n-butylsulfonylchloride instead. A colorless, waxy solid of excellent purity was obtained in 65% yield without purification; mp 46-50° C.; ¹³ C NMR (300 MHz, CDCl₃) δ 172.64, 67.29, 52.56, 51.99, 47.83, 38.40, 25.57, 21.52, 13.55; Anal. Calc. for C₉ H₁₉ NO₅ S: C, 42.67; H, 7.56; N, 5.53; S, 12.66. Found: C, 42.69; H, 7.59; N, 5.36; S, 12.78.

Part B. Methyl 3-oxo-4-(n-butylsulfonamido)butanoate

The immediately preceeding alcohol was oxidized as described for Example 359, Part C, to give a 57% yield of a colorless solid; mp 53-55° C.; Anal. Calc. for C₉ H₁₇ NO₅ S: C, 43.02; H. 6.82; N, 5.57; S, 12.76. Found: C, 42.68; H, 7.03; N, 5.74; S, 13.06.

Part C. Methyl 3(R,S)-3-amino-4-(n-butylsulfonamido)butanoate

This compound was prepared analogous to Example 350, Part B, using the product from Part B above (1.20 g, 4.8 mmol) yielding 0.26 g yellow oil; 1H NMR (300 MHz, CDCl₃) δ 3.70 (s, 3H), 3.38 (m, 1H), 3.24-3.13 (m, 1H), 3.02 (m, 4H), 2.58-2.52 (dd, J=16, J'=11, 1H), 1.79 (m, 2H), 1.24 (m, 2H), 0.95 (t, 3H); MS (NH4-DCI) Calc. for (M+H)⁺ : 271. Found: 271.

Part D. Methyl-3(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidine)phenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonylamidc)butanoate

To a solution 3-[4-(N-t-butoxycarbonylamidine)phenyl]isoxazolin-5-ylacetic acid (0.24 g, 0.83 mmol) in DMF (20 ml), the product from Part C above (0.29 gr, 0.83 mmol), TBTU (0.27 g, 0.83 mmol), and Et₃ N (0.46 ml, 3.3 mmol) was added. After stirring 4 h at room temperature, the reaction mixture was diluted with EtOAc, extracted with pH 4 buffer (potassium hydrogen phthalate), saturated NaHCO₃, brine, then dried (NaSO₄). Concentration, followed by chromatography over silica gel in 100% EtOAc, yielded 1.17 g of a white foam; MS (NH3-DCI) Calc. for (M+H)⁺ : 582.3. Found: 582; IR(KBr) 3312, 2338, 1620, 1144 cm⁻¹.

Part E. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonylamido)butanoate  trifluoroacetic acid

To a solution of the product from Part D above (0.22 g, 0.37 mmol) in DCM (10 ml), trifluoroacetic acid (2.2 ml) was added. The reaction mixture was stirred 2 h at room temperature, triturated with Et₂ O, and the resulting precipitate was chromatographed over silica gel in 20% MeOH in CHCl₃ to yield 0.20 g white solid; HRMS, e/z Calc. for (M+H)⁺ : 482.2073. Found: 482.2090; mp=178-184° C.

EXAMPLE 365 Methyl {5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate  trifluoroacetic Acid Salt

Part A. Dimethyl 3-aminoglutarate  hydrochloric acid salt

This product was prepared similarly to Example 359, Part A, from β-glutamic acid to yield the diester as a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H)⁺ : 176.0923. Found: 176.0933.

Part B. Methyl {5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate

Prepared analogous to Example 359, Part E, to yield 32% of a white solid; IR(KBr) 3306, 2338, 1738, 1656, 1620 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 505.2298. Found: 505.2283.

Part C. Methyl {5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate  trifluoroacetic acid salt

Prepared analogous to Example 348, Part F, yielding 83% white solid; IR(KBr) 3316, 3102, 2340, 1736, 1670 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 405.1774. Found: 405.1775.

EXAMPLE 368 Methyl 3(R,S)-{5(RS)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)-pentanoate  trifluoroacetic Acid Salt

Part A. Dimethyl 3-(R,S)-aminoadipate  hydrochloric acid salt

This product was prepared as in Example 359, Part A, from β-aminoadipic acid to yield a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H)⁺ : 190.1079. Found: 190.1080.

Part B. Methyl-3(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarhonylamidine)phenyl)isoxzalin-5-ylacetyl]amino}-4-(methoxycarbonyl)pentanoate

This product was prepared similarly as in Example 362, Part D, using the product from Part B above (0.70 g, 3.1 mmol) instead to yield 1.17 g of a white foam; HRMS, e/z Calc. for (M+H)⁺ : 519.2454. Found: 519.2459; Anal. Calc. for C₂₅ H₃₄ N₄ O₈ : C, 57.90; H, 6.61; N,10.80. Found: C, 57.73; H, 6.51; N, 10.86.

Part C. Methyl-3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amine}-4-(methoxyacarbonyl)pentanoate  trifluoroacetic acid salt

This product was prepared as in Example 362, Part E, using the product from Part C above (1.00 g, 1.9 mmol) to yield 0.9 g white solid; HRMS, e/z Calc. for (M+H)⁺ : 419.1930. Found: 419.1921; mp=214-215° C. (decomposes).

EXAMPLE 375 Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine

Part A. Preparation of 2-(Methoxy-2-oxoethyl)piperidine

Pyridylacetic acid hydrochloride (10.00 g, 57.6 mmol) and platinum(IV) oxide (1.00 g, 4.4 mmol) were shaken in a mixture of 75 ml acetic acid, 75 ml methanol, and 10 ml conc. HCl on Parr under 60 psi hydrogen at room temperature overnight. The mixture was then filtered through Celite, and the filtrate evaporated under reduced pressure to yield 8.42 g (75.9%) of the title compound as an off-white solid. MS (NH₃ -CI/DDIP): m/e 158 (M+H)⁺. ¹ H NMR (300 MHz, CDCl₃): δ 1.50-1.96 (m, 6H); 2.80 (m, 2H); 3.20-3.60 (m, 3H); 3.76 (s, 3H). ¹³ C NMR (60 MHz, d₆ -DMSO): δ 21.94; 28.05; 37.46; 40.49; 44.12; 57.33; 52.74; 170.39.

Part B. Preparation of 2-(R,S)-2-(Methoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperidine

To 2.00 g (8.69 mmol) of 3-(4-cyanophenyl)-isoxazolin-5-yl acetic acid in 100 ml anhydrous DMF was added 1.36 g (8.69 mmol) of 2-(methoxy-2-oxoethyl)piperidine, 2.80 g (8.69 mmol) of TBTU, and 6.05 ml (34.7 mmol) of diisopropylethylamine. After stirring for 6 hrs, the reaction mixture was diluted with ethyl acetate and washed with 5% aqueous citric acid solution, water, 5% aqueous NaHCO₃ solution, and saturated NaCl solution. The organic layer was dried over Na₂ SO₄ and filtered. The filtrate was evaporated under reduced pressure to give the crude product as a yellow foam. Purification by flash column chromatography on silica gel using 25-75% ethyl acetate in hexane yielded 1.54 g (48%) of the title compound as a yellow foam. One diastereomer (racemic) was isolated from the mixture. MS (NH₃ -CI/DDIP): m/e 370 (M+H)⁺. ¹ H NMR (300 MHz, CDCl₃): δ 1.42-1.76 (m, 6H); 2.60 (m, 2H); 2.77-3.01 (m, 3H); 3.05-3.26 (m, 2H); 3.56-3.70 (m, 4H); 4.50 (m, 1H); 5.20 (m, 1H); 7.69 (d, J=8.4 Hz, 2H); 7.77 (d, J=8.4 Hz, 2H).

Part C. Preparation of 2-(Methoxy-2-oxoethyl)-1-{N- [3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine, (racemic diastereomer A)

HCl gas was bubbled for 2 hrs through a solution of 1.02 g (2.80 mmol) of the product of part B above in 30 ml of anhydrous MeOH cooled in an ice bath. The reaction flask was then sealed with Teflon tape and warmed to room temperature while stirring overnight. MeOH was evaporated under reduced pressure and then under vacuum to give the intermediate imidate as a yellow foam. MS (ESI): m/e 402 (M+H)⁺. It was then stirred with 8.07 g (84.0 mmol) of (NH₄)₂ CO₃ in 30 ml anhydrous EtOH overnight in a sealed reaction flask. After filtering, the filtrate was evaporated under reduced pressure to give the crude product as a yellow foam, which was then purified by flash column chromatography using 5-17% MeOH in CH₂ Cl₂ to give 0.29 g (26.8%) of the title compound as a yellow solid. MS (ESI): m/e 387 (M+H)⁺. ¹ H NMR (300 MHz, d₆ -DMSO): δ 1.57-1.67 (br., 6H); 2.46-2.90 (m, 5H); 3.16 (m, 2H); 3.53-3.64 (m, 4H); 4.36 (br. m, 1H); 5.07 (br. m, 1H); 7.89 (m, 4H); 9.38 (br. s, 3H).

Part D. Preparation of 2-Carboxymethyl-1-{N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine, (Racemic Isomer A)

To a solution of 0.08 g (0.2 mmol) of the product isolated in Part C above in 5 ml anhydrous THF at ambient temperature was added 0.5 ml (0.5 mmol) of 1.0 M solution of NaOTMS in THF. After stirring overnight, solvent was evaporated under reduced-pressure to give a yellow solid, which was recrystallized from MeOH and Et₂ O to give 0.05 g (64.9%) of the title compound as a yellow powder. MS (ESI): m/e 373 (M+H)⁺. ¹ H NMR (300 MHz, CD₃ OD): δ 1.68 (br., 6H); 2.56 (m, 2H); 2.72 (m, 3H); 2.94 (m, 2H); 3.57 (m, 4H); 4.46 (br., 1H); 5.18 (br., 1H); 7.84 (m, 4H).

EXAMPLE 377 Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine

Part A. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}azepine

From 0.50 g (2.17 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.40 g (2.17 mmol) of 2-(ethoxy-2-oxoethyl)azepine, 0.70 g (2.17 mmol) TBTU, and 1.51 ml (8.70 mmol) diisopropylethylamine, 0.73 g (84.6 %) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH₃ -CI/DDIP): m/e 398 (M+H)⁺. ¹ H NMR (300 MHz, CDCl₃): δ 1.26 (m, 11H); 1.83 (br., 2H); 2.05 (m, 1H); 2.18-2.65 (m, 2H); 2.76-2.85 (m, 1H); 3.04 (m, 2H); 3.62 (s, 1H); 4.08 (m, 2H); 5.22 (m, 1H); 7.68 (d, J=8.4 Hz, 2H); 7.78 (d, J=8.4 Hz, 2H).

Part B. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-{5-(R,S) -N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine

From 0.73 g (1.84 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}azepine, using EtOH as the solvent, 0.42 g (61.6%) of the title compound was obtained following the procedure of Example 375, Part C. MS (NH3-CI/DDIP): m/e 415(M+H)⁺. ¹ H NMR (300 MHz, d₆ -DMSO): δ 1.18 (m, 3H); 1.38 (m, 2H); 1.70 (m, 4H); 2.08 (br., 2H); 2.66 (m, 2H); 3.02-3.26 (m, 2H); 3.60 (br. m, 2H); 4.05 (m, 2H); 4.58 (,m, 1H); 5.10 (m, 1H); 7.90 (m, 4H); 9.38 (br. s, 3H).

Part C. Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine

From 0.16 g (0.35 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine and using 0.89 ml (0.89 mmol) of 1.0 M solution of NaOTMS in THF, 0.12 g (82.9%) of the title compound was obtained following the procedure of Example 375, Part D. MS (NH₃ -DCI): m/e 387 (M+H)⁺.

EXAMPLE 400 Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one

Part A. Preparation of 3-(R,S)-(Ethoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one

From 1.00 g (4.34 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.81 g (4.34 mmol) of ethyl 2-piperazin-3-one acetate, 1.39 g (4.34 nmol) TBTU, and 3.02 ml (17.40 mmol) diisopropylethylamine, 1.08 g (62.4%) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH₃ -CI/DDIP): m/e 399 (M+H)⁺. ¹ H NMR (300 MHz, CDCl₃): δ 1.26 (m, 3H); 2.71-3.65 (br., 9H); 3.87 (br. m, 1H); 4.16 (m, 2H); 5.01 & 5.09 (two t, J=5.0, 5.1 Hz, 1H); 5.20 (m, 1H); 7.00 & 7.12 (two br., 1H); 7.77 (m, 4H).

Part B. Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one

From 1.08 g (2.71 mmol) of 3-(R,S)-(ethoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one, 0.30 g (27.6%) of the title compound was obtained, following the procedure of Example 375, Part C. MS (ESI): m/e 402 (M+H)⁺. ¹ H NMR (300 MHz, d₆ -DMSO): δ 2.70-3.67 (m, 12H); 3.91 (br., 1H); 4.87 & 4.64 (two m, 1H); 5.06 (m., 1H); 7.88 (m, 4H); 8.16 (br., 1H); 9.40 (br. s, 3H).

EXAMPLE 434 Preparation of (S)-N.sup.α -[3-(4-Amidinoehenyl)-isoxazolin-5-(R,S) -ylacetyl]-α-aspart-N-(2-phenylethyl)amide, trifluoroacetic Acid Salt

Part A. Preparation of (S)-N.sup.α -(Benzyloxycarbonyl)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide

To a solution of (S)-N-(Benzyloxycarbonyl)-β-(O-t-butyl)-aspartic acid (BACHEM-Bioscience Inc) (3.20 g, 9.9 mmol) in DCM (25 mL), was added phenethylamine (1.34 g, 11.1 mmol); followed by DEC (2.10 g, 10.9 nmol). The reaction mixture was stirred overnight at room temperature, affording a pale yellow solution. This solution was washed with water, 1M HCl, 5% NaHCO₃ and sat. NaCl, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give 4.28 g (100%) of amide, which was of sufficient purity to be carried on to the next step; ¹ H NMR (300 MHz, CDCl₃) δ 7.35 (s, 5H), 7.17-7.35 (bm, 5H), 6.52 (bs, 1H), 5.93 (bd, J=8.1 Hz, 1H), 5.10 (s, 2H), 4.46 (bm, 1H), 3.50 (dd, J=13.9, 6.2 Hz, 2H), 2.92 (dd, J=17.0, 4.2 Hz, 1H), 2.78 (t, J=7.1 Hz, 2H), 2.57 (dd, J=17.0, 6.4 Hz, 1H), 1.42 (s, 9H); Mass Spectrum (NH₃ -DCI, e/z, relative abundance) 444, (M+NH₄)⁺, 100%; 427, (M+H)⁺, 4%.

Part B. Preparation of (S)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide

A solution of (S)-N-(benzyloxycarbonyl)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (4.09 g, 9.58 mmol) in ethyl alcohol (30 mL) was hydrogenated under atmospheric pressure using 10% palladium on carbon catalyst (1.0 g) for 90 minutes. The catalyst was filtered and the filtrate concentrated in vacuo to give 2.80 g of an amber oil, which was purified by flash chromatography (5% MeOH/DCM), affording 2.13 g (76%) of the free amine as a solid product; ¹ H NMR (300 MHz, CDCl₃) δ 7.44(bs, 1H), 7.20-7.35 (m, 5H), 3.61 (dd, J=8.4, 3.7 Hz, 1H), 3.52 (dd, J=13.2, 7.0 Hz, 1H), 2.80-2.90 (m, 3H), 2.46 (dd, J=16.7, 8.4 Hz, 1H), 1.58 (bs, 2H), 1.45 (s, 9H); Mass Spectrum (ESI, e/z, relative abundance) 293, (M+H)⁺, 37%; 237, (M+H-C₄ H₈)⁺, 100%.

Part C. Preparation of Methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt

A suspension of 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-ylacetic acid (23.1 g, 100 mmol) in 200 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a clear solution was obtained. The total addition time was about three hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 600 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25° C. for 21/2 hours. The slurry was then diluted with an additional 100 mL of chilled anhydrous ether. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 23.3 g (73%) of the hydrochloride salt; ¹ H NMR (300 MHz, CDCl₃) δ 12.9 (bs, 1H) 12.2 (bs, 1H), 8.46 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 5.20 (bm, 1H), 4.59 (s, 3H), 3.74 (s, 3H), 3.53 (dd, J=16.8, 10.6 Hz, 1H), 3.15 (dd, J=16.8, 7.7 Hz, 1H), 2.90 (dd, J=16.1, 6.2 Hz, 1H), 2.70 (dd, J=16.1, 7.3 Hz, 1H), 1.77 (bs, 1H); Mass Spectrum (NH₃ -CI/DDIP, e/z, relative abundance) 277, (M+H)⁺, 100%.

Part D. Preparation of methyl 3-(4-amidinophenyl)-5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt

A suspension of methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate hydrochloride (22.9 g, 73.0 mmol) in 500 mL of 1M ammonia in anhydrous methanol was stirred at room temperature for 14 hours during which time all solids dissolved. The solution was concentrated in vacuo to give 22.1 g (100%) of crude hydrochloride salt as a tan solid; ¹ H NMR (300 MHz, CDCl₃) δ 9.6-9,2 (b), 7.91 (d, J=8.8, 2H), 7.87 (d, J=8.8, 2H), 5.08 (bm, 1H), 3.64 (s, 3H), 3.3-3.1 (m, 2H), 2.8 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 264, (M+H)⁺, 100%.

Part E. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate

To a solution of 21.6 g (72.5 mmol) of methyl 3-(4-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part D) in 350 ml DMF cooled with an ice bath was added 20.2 ml (145 mmol) of triethylamine and 17.4 g (79.8 mmol) of di-tert-butyl dicarbonate. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into 1500 ml water while stirring. A while precipitate formed and was then filtered and dried on the filter under nitrogen to give 19.6 g (74.8%) of the title compound as a white solid. MS (ESI): m/e 362 (M+H)⁺ ; 306 (M+H-tBu)⁺. ¹ H NMR (300 MHz, d₆ -DMSO): δ 1.56 (s, 9H); 2.68 (dd, J=6.1, 6.1 Hz, 1H); 2.90 (dd, J=6.1, 6.1 Hz, 1H); 3.14 (dd, J=6.8, 6.8 Hz, 1H); 3.56 (dd, J=6.8, 6.8 Hz, 1H); 3.74 (s, 3H); 5.14 (m, 1H); 7.70 (d, J=8.4 Hz, 2H); 7.90 (d, J=8.4 Hz, 2H). ¹³ C NMR (60 MHz, d₆ -DMSO): δ 28.46; 39.31; 39.58; 51.98; 77.89; 78.35; 126.91; 128.51; 132.79; 136.24; 156.86; 164.04; 165.76; 170.93.

Part F. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazolin-5ylacetic Acid

To a solution of 18.95 g (52.4 mmol) of methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part E) in 500 ml methanol was added 2.42 g (57.7 mmol) of lithium hydroxide monohydrate in 75 ml water at 22° C. The mixture was stirred at 22° C. for 16 hours and then filtered; the filtrate was then evaporated under reduced pressure to remove methanol. The residual aqueous phase was cooled with an ice bath and acidified with 6 N and 1 N HCl to pH=4. A white solid precipitated and it was left at -4° C. overnight. The solid was filtered and dried on the filter under nitrogen to give 17.74 g (97.4%) of the title compound as an off-white powder. MS (ESI): m/e 348 (M+H)⁺ ; 292 (M+H-tBu)⁺. ¹ H NMR (300 MHz, d₆ -DMSO): δ 1.50 (s, 9H); 2.68 (d, J=7.0 Hz, 2H); 3.22 (dd, J=7.2, 7.2 Hz, 1H); 3.62 (dd, J=6.8, 7.2 Hz, 1H); 5.04 (m, 1H); 7.78 (d, J=8.4 Hz, 2H); 7.94 (d, J=8.4 Hz, 2H). ¹³ C NMR (60 MHz, d₆ -DMSO): δ 28.27; 39.30; 40.44; 78.39; 81.55; 126.87; 129.43; 132.78; 133.87; 156.76; 158.61; 165.58; 171.91.

Part G. Preparation of (S)-N-[.sup.α -(4-N-Boc-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-β-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide

To a suspension of (S)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (0.30 g, 1.0 mmol), 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (0.35 g, 1.0 mmol), and TBTU (0.32 g, 1.0 mmol) in EtOAc (20 mL), was added triethy amine (460 μL, 0.33 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 4.5 hr. It was diluted with EtOAc (20 mL), washed with pH 4 buffer, water, 5% NaHCO₃ and sat. NaCl, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give 0.58 g of solid. The crude product was purified by flash chromatography (100% EtOAc), affording 0.51 g (81%); ¹ H NMR (300 MHz, CDCl₃) δ 7.89 (t, J=8.1 Hz, 2H), 7.69 (m, 2H), 7.25-7.3 (m, 3H), 7.15-7.25 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 6.65-6.80 (dt, 1H), 5.10 (bm, 1H), 4.71 (bm, 1H), 3.4-3.7 (bm, 3H), 3.1-3.3 (octet, 1H), 2.75-2.95 (m, 3H), 2.5-2.65 (m, 3H), 1.56 (s, 9H), 1.44, (d, 9H); Mass Spectrum.(ESI, e/z, relative abundance) 622, (M+H)⁺, 100%.

EXAMPLE 435 Preparation of (S)-N.sup.α -[3-(4-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-α-aspart-N-(2-phenylethyl)amide, Trifluoroacetic Acid Salt

A solution of (S)-N-[3-(4-N.sup.α -Boc-amidinophenyl)-isoxazolin-5-ylacetyl]-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (160 mg, 0.26 mmol) in trifluoroacetic acid (10 mL) and DCM (10 mL) was stirred at room temperature for three days. The solution was concentrated in vacuo to give 150 mg of product; ¹ H NMR (300 MHz, CDCl₃) δ 9.40 (bs, 2H), 9.26 (bs, 2H), 8.33 (t, J=8.6, 1H), 7.85-8.0 (m, 1H), 7.88 (s, 4H), 7.3 (m, 1H), 7.28 (d, J=7.1, 2H), 7.20 (d, J=7.1, 2H), 5.07 (bm, 1H), 4.56 (bm, 1H), 3.5-3.6 (octet, 1H), 3.26 (bt, J=7.0, 2H), 3.2 (m, 1H), 2.70 (bt, J=7.0, 2H), 2.6-2.65 (bm, 2H), 2.4-2.5 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 466, (M+H)⁺, 100%.

EXAMPLE 445 N² -(β-Styrylsulfonyl)-N³ -[3-(4-amidino-phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 500 (M+H)⁺, (100%).

EXAMPLES 473A AND 473B Resolution of Methyl N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate Trifluoroacetic Acid Salt and Methyl N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate Trifluoroacetic Acid Salt

The mixture was initially purified on a Pirkle DNBPG column using 10%HOAc/20%EtOH/70% hexane as the eluting solvent. The column temperature was maintained at 45° C., the flow rate at 1.5 ml/min, and the detector set at 280 nm. The diastereomers were then separated on a chiralcel OD-25×2cm column using an eluting solvent of 0.1%TFA/20%MeOH/80%CO₂. The column temperature was maintained at 30° C., the flow rate at 13 ml/min, the pressure at 175 atm, and the detector was set at 280 nm. Injections were made on 23mg of sample. Over the two columns a total of 300 mg was injected giving 59 mg of the R isomer, Ex. 473A (HRMS calc'd for C₂₃ H₂₇ N₅ O₆ S 502.176031 Found: 502.175508) and 85 mg of the S isomer, Ex. 473B (HRMS calc'd for C₂₃ H₂₇ N₅ O₆ S 502.176031 Found: 502.176358).

EXAMPLE 473C N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionic Acid

Part A: Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminoprotionate

Into a solution of 3-(4-cyanophenyl)isoxazolin-5-S-ylacetic acid (1.82 g, 7.90 mmol, obtained as described in Es. 314A, part F) in DMF (50 ml) was added methyl-N² -3-methylphenylsulfonyl-L-2,3-diaminopropionate HCl salt (2.77 g, 7.90 mmol), TBTU (2.53 g, 7.90 mmol), and Hunigs base (2.75 ml, 15.8 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (500 ml) and washed one time with water (200 ml), one time with sat'd NaHCO₃ (200 ml), one time with 0.1N HCl (200 ml), dried (MgSO₄), filtered, and concentrated. Column chromatography on silica gel using 10% EtOAc/hexane as the eluting solvent gave 1.99 g (52%) of the desired material as an off-white foam. ¹ H NMR: (CDCl₃): δ 7.81-7.78 (d, 2H, J=8.4 Hz); 7.16-7.67 (d, 2H, J=8.8 Hz); 7.61-7.58 (m, 2H); 7.39-7.37 (d, 2H, J=5.1 Hz); 6.35-6.30 (m, 1H); 5.54-5.52 (d, 1H, J=7.7 Hz); 5.18-5.17 (m, 1H); 4.00-3.96 (m, 1H); 3.62-3.50 (m, 3H); 3.57 (s, 3H); 3.27-3.19 (dd, 1H, J-7.7, 17.0 Hz); 2.78-2.70 (dd, 1H, J=5.9, 14.8 Hz); 2.64-2.57 (dd, 1H, J=6.6, 14.6 Hz); 2.42 (s, 3H).

Part B: Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionate hydrochloride

Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-cyanophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate was dissolved in 100 ml absolute ethanol at 0° C. and a stream of HCl gas was bubbled through the solution for two hours. The reaction vessel was sealed and after sitting at room temperature for 16 hours the volatiles were removed in vacuo. The residue was then diluted with 100 ml of absolute ethanol, ammonium carbonate (9.6 g, 0.123 mol) was added and after stirring for 16 hours the reaction mixture was filtered and concentrated in vacuo. Column chromatography on silica using a gradient elution from 5%MeOH/CH₂ Cl₂ to 20%MeOH/CH₂ Cl₂ gave 0.762 g (37%) of the desired amidine as a white solid. ¹ H NMR (CDCl₃): δ 8.23-8.20 (m, 1H); 7.91-7.85 (m, 4H); 7.57-7.54 (m, 2H); 7.49-7.46 (m, 2H); 5.00-4.94 (m, 1H); 4.08-3.86 (m, 1H); 3.59-3.49 (m, 1H); 3.39 (s, 3H); 3.38-3.29 (m, 3H); 2.49 (s, 3H); 2.50-2.45 (m, 2H). HRMS: calc'd for C₂₃ H₂₇ N₅ O₆ S 502.176031 found 502.175992. [α]_(D) =+48.88° (c=0.180, MeOH).

Part C: N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)5(S)-yl]acetyl-S-2,3-diaminopropionic acid

The compound of Ex 473C, part B (0.077 g., 0.14 mmol) was dissolved in MeOH (4 ml). To the resulting solution was added a solution of lithium hydroxide (0.0066 g., 0.158 mmol) in water (4 ml) and the mixture was stirred overnight at room temperature. The methanol was removed by evaporation in vacuo, and the product precipitated from the aqueous as a white solid (0.026 g., 35%). HRMS calcd for C₂₂ H₂₅ N₅ O₆ S: 488.160381; found: 488.160827.

EXAMPLE 473D Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate Hydrochloride

Part A: Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-cyanophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate

This compound was synthesized from 3-(4-cyanophenyl)isoxazolin-5-(R)-ylacetic acid (3.07 g, 0.011 mol, obtained as described in Ex. 314B, part B) using the same procedure as for example 473C, part A. Yield 41%. Theory: C 57.02, H 4.99, N 11.56 Found: C 56.83, H 4.87, N 11.45.

Part B: Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate hydrochloride

This compound was synthesized from Methyl-N² -3-methylphenylsulfonyl-N³ -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate using the same procedure as for example 473C, part B. Yield 49%. HRMS Calc'd for C₂₃ H₂₇ N₅ O₆ S 502.176031 Found: 502.174103.

EXAMPLE 478a N² -2,4,6-trimethylphenylsulfonyl-N³ -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ H NMR (DMSO-d₆) δ: 9.37 (s, 2H), 9.06 (s,2H), 8.10 (q,J=6.22 Hz, 1H), 7.98(d, J=9.52 Hz, 1H), 7.87 (s,4H),6.98 (d, J=4.40 Hz, 2H), 4.99(m, 1H), 3.85 (m, 1H), 3.59-3.0 (m, 4H), 2.55 (s, 6H), 2.41 (m,2H), 2.23 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 516.3 (100)%, High Res Mass Spectrum (M+H)⁺ calculated 516.190344, found 516.189999.

EXAMPLE 479a N² -2-chlorophenylsulfonyl-N³ -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid

M.P. 138-140° C. ¹ H NMR (DMSO-d₆) δ: 9.39 (s, 2H), 9.27 (s, 2H) 8.30 (dd, J=4.40, 9.15 Hz 1H), 8.22 (m, 1H), 7.96 (d, J=6.95 Hz, 1H), 7.88 (s, 4H), 7.65 (m,2H), 7.59 (m 1H), 5.04 (m, 1H), 4.03 (m 1H), 3.58 (m 1H), 3.38 (m, 1H), 3.24 (m, 2H), 2.59 (dd, j=6.22, 14.28 Hz, 1H), 2.43 (m, 1H) ppm Mass Spectrum (ESI) m/z (M+H)⁺ 508.1 (100%), High Res Mass Spectrum (M+H)⁺ calculated 508.107096, found 508.106929.

EXAMPLE 485a N.sup.α -2,3,5,6-tetramethylthenylsulfonyl-N³ -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

M.P.148-150° C., ¹ H NMR (DMSO-d₆) δ: 9.38 (s, 2H), 9.29 (s,2H), 8.09 (m, 1H), 7.97 (dd, J=4.40, 9.15 Hz, 1H), 7.85 (s, 4H), 7.15 (d, J=7.32 Hz, 1H), 4.98 (m, 1H), 3.88 (q, J=6.96, 15.75 Hz, 1H), 3.56 (m, 1H), 3.34-3.08 (m, 4H), 2.43 (s,6H), 2.39 (m, 1H), 2.19 (s,3H), 2.18 (s, 3H) ppm. Mass Spectrum (ESI) m/z (M+H)⁺ 530.2 (100%); High Res Mass Spectrum (M+H)⁺ calculated 530.208668; found 530.208357.

EXAMPLE 490a N² -n-Propanesulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: Methyl N² -n-Propanesulfonyl-N³ -Boc-(S)-2,3-diaminopropionate

To a solution of methyl N³ -Boc-(S)-2,3-diaminopropionate (prepared in Ex 20, Part C, 410 mg, 1.88 mmol)-in CH₂ Cl₂ (5 mL) at 0° C. was added propanesulfonyl chloride (0.21 mL, 1.9 mmol) and Et₃ N (0.35 mL, 2.5 mmol) and the resulting mixture allowed to warm to room temperature overnight (18 h). The mixture was washed with 0.1 M HCl, sat. NaHCO₃ and brine, dried (MgSO₄), and concentrated to give 530 mg (87%) of the desired sulfonamide as a viscous oil; CIMS (e/z, relative intensity): 342 (M+H)⁺, 100%.

Part B: Methyl N² -n-Propanesulfonyl-(S)-2,3-diaminopropionate Hydrochloride Salt

To neat methyl N² -n-propanesulfonyl-N³ -Boc-(S)-2,3-diaminopropionate (520 mg, 1.60 mmol) was added 4 M HCl/dioxane (5 mL, 20 mmol). The resulting solution was stirred at room temperature for 4 h, then it was concentrated in vacuo, giving an oil. Trituration with ether (3×10 mL) followed by drying under vacuum afforded 383 mg (92%) of the desired amine; CIMS (e/z, relative intensity): 225 (M+H)⁺, 100%.

Part C: Methyl N² -n-propanesulfonyl-N³ -[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate

To a suspension of 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (prepared in Example 32, 252 mg, 0.725 mmol), methyl N² -n-propanesulfonyl-(S)-2,3-diaminopropionate hydrochloride (189 mg, 0.726 mmol) in DMF (5 mL) was added Et₃ N (0.30 mL, 2.2 mmol) and TBTU (233 mg, 0.726 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (30 mL). It was washed with water (4×20 mL), sat. NaHCO₃ (30 mL), sat. NaCl and dried (MgSO₄). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 292 mg (73%) of the desired amide; MS (ESI, e/z, relative intensity): 554 (M+H)⁺, 100%.

Part D: Methyl N² -n-Propanesulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate TFA Salt

To a solution of methyl N² -n-propanesulfonyl-N³ -[3-(4- (N- t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (284 mg, 0.513 mmol) in CH₂ Cl₂ (4 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3×5 mL). The resulting white powder was then placed under vacuum until constant weight was achieved, giving 260 mg (89%) of the desired benzamidine; MS (ESI, e/z, relative intensity): 454 (M+H)⁺, 100%.

Part E: N² -n-Propanesulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(g)-2,3-diaminopropionic Acid TFA Salt

To a solution of methyl N² -n-propanesulfonyl-N³ [3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (100 mg, 0.176 mmol) in MeOH (1 mL) was added 0.5 M LiOH (0.5 mL, 0.25 mmol) and the reaction stirred at room temperature overnight (18 h). The resulting mixture was concentrated in vacuo, redissolved in water and the pH adjusted to 4 using 1 M HCl. Purification on reversed phase HPLC gave 10 mg (10%) of the desired carboxylic acid; MS (ESI, e/z, relative intensity): 440 (M+H)⁺, (100%).

EXAMPLE 492a N² -p-isopropylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ: 9.37(1H, s), 9.09(1H, s), 8.15(2H, m), 8.78(4H, d, J=1.465 Hz), 7.09(2H, d, J=8.423 Hz), 7.44(2H, m), 4.98(1H, m), 3.93(1H, m), 3.59(2H, m), 3.50(2H, m), 3.22(2H, m), 2.98(1H, m),2.45(2H, m), 1.22(6H, m)ppm; ESI mass spectrum 516.3 (M+H, 100)⁺ free base.

EXAMPLE 496 Methyl N₂ -(2,2-diphenyl-1-ethenesulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoeropionate, Trifluoroacetic Acid Salt

Part A: Methyl N² -(2,2-diphenyl-1-ethenesulfonyl)-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate (255 mg, 1.17 mmol) and 2,2-diphenylethylenesulfonyl chloride (Hasegawa and Hirooka, J. Chem. Soc. Japan 48, 1513-1518 (1975); 391 mg, 1.40 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.25 mL, 1.76 mmol). After 22 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 240 mg (46%) of product. NMR (CDCl₃) δ 7.42-7.20 (10H), 6.81 (s, 1H), 5.24 (bd, 1H), 4.87 (bs, 1H), 3.95 (q, 1H), 3.72 (s, 3H), 3.50-3.42 (2H), 1.44 (s, 9H); mass spec (NH₃ -CI) m/z 466.54 (M+NH4⁺, 100%).

Part B: Methyl N² -(2,2-diphenyl-1-ethenesulfonyl)-(S)-2,3-diaminopropionate TFA salt.

The product of Part A (210 mg, 0.468 mmol) was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product. (222 mg, 100%). NMR (DMSO-d₆) δ 8.02 (bs, 3H), 7.40 (m, 5H), 7.23 (m, 4H), 7.00 (s, 1H), 4.26 (m, 1H), 3.71 (s, 3H), 3.20 (m, 1H), 2.98 (m, 1H).

Part C: Methyl N² -(2,2-diphenyl-1-ethenesulfonyl)-N³ -[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate.

The product of part B (220 mg, 0.46 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (from Example 434 , part F; 160 mg, 0.46 mmol), according to the procedure of example 651, Part A, to provide the title product (215 mg, 68%). NMR (CDCl₃) δ 7.84 (m, 2H), 7.64 (m,2H), 7.40-7.18 (10H), 6.75 (s, 1H), 6.30 (m, 1H), 5.30 (m, 1H), 5.04 (m,1H), 4.00 (1H), 3.78 (s,3H), 3.62-3.40 (4H), 3.10 (m, 1H), 2.70-2.50 (2H), 2.04 (s, 1H), 1.58 (s, 9H); mass spec (ESI) m/z 690.2 (M+H⁺, 100%).

Part D: Methyl N² -(2,2-diphenyl-1-ethenesulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part C (210 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (150 mg, 80%). NMR (DMSO-d₆) δ 9.39 (bs,2H), 9.05 (bs,2H), 8.22 (m, 1H), 8.00 (m, 1H), 7.85 (s,4H), 7.40 (m,6H), 7.20 (m,4H), 6.89 (s, 1H), 5.00 (m, 1H), 4.00 (m, 1H), 3.70-3.18 (5H), 3.62 (2s,3H); mass spec (ESI) m/z 590.2 (M+H⁺, 100%)

EXAMPLE 511 Methyl N² -(N,N-dimethylsulfamoyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt

Part A: Methyl N² -(N,N-dimethyl sulfamoyl)-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate (400 mg, 1.80 mmol) and Dimethylsulfamoyl chloride (0.24 mL, 2.20 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.38 mL, 2.20 mmol). After 18 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 283 mg (49%) of product. NMR (CDCl₃) δ 5.23 (bd, 1H), 4.90 (m, 1H), 4.06 (m, 1H), 3.80 (s, 3H), 3.52 (bt, 2H), 2.80 (s,6H), 1.42 (s, 9H); mass spec (NH₃ -CI) m/z 343.0 (M+NH₄ ⁺, 100%).

Part B: Methyl N² -(N,N-dimethyl sulfamoyl)-(S)-2,3-diaminopropionate TFA salt.

The Product of Part A was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product (294 mg, 100%). NMR (DMSO-d₆) δ 6.52 (bs, 2H), 4.4-3.9 (2H), 3.8 (bs, 3H), 2.93 (bs, 6H).

Part C: Methyl N² -(N,N-dimethyl sulfamoyl)-N³ -[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-L-2,3-diaminoiroDionate.

The product of part B (200 mg, 0.61 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (from Example 434, part F; 212 mg, 0.61 mmol), according to the procedure of Example 651, Part A, to provide the title product (203 mg, 61%). NMR (CDCl₃) δ 7.78 (m, 2H), 7.42 (bt, 2H), 7.00 (m, 1H), 5.92 (m, 1H), 5.04 (m, 1H), 3.80 (2s, 3H), 3.64 (m, 2H), 3.40 (m, 1H), 3.05 (m, 1H), 2.80 (2s, 6H), 2.74 (m, 1H), 2.60 (m, 1H), 2.02 (s, 3H), 1.60 (s, 9H); mass spec (ESI) m/z 555.1 (M+H⁺, 100%).

Part D: Methyl N² -(N,N-dimethyl sulfamoyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-L-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part C (183 mg, 0.329 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (159 mg, 85%). NMR (DMSO-d₆) δ 9.40 (bs, 2H), 9.00 (bs, 2H), 8.22 (m, 1H), 7.82 (s, 4H), 5.00 (m, 1H), 3.95 (m, 1H), 3.68 (2s, 3H), 3.60 (m, 2H), 3.20 (m, 4H), 2.80 (s, 6H); mass spec (ESI) m/z 455.1 (M+H⁺, 100%).

EXAMPLE 512 Methyl N² -(m-toluenesulfonyl)-N³ -[3-(4-amidino-2-fluorophenyl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt

Part A: 3-Fluoro-4-methylbenzamide

3-Fluoro-4-methylbenzoic acid (10 g, 65 mmol) was boiled in thionyl chloride (100 ML) under a drying tube for 2.5 h. The excess SOCl₂ was removed by distillation. The oily acid chloride product was diluted with CH₂ Cl₂ (100 mL) and cooled in an ice bath. Conc. aq. NH₃ (20 mL) was added dropwise, and stirring continued at 0° C. for 0.5 h. The CH₂ Cl₂ was removed in vacuo, then the residue was diluted with EtOAc. The mixture was extracted with sat. aq. Na₂ CO₃ (2x), H₂ O, and brine, dried (MgSO₄), and concentrated to yield 9.9 g of a pale yellow solid; mp 161°-163° C.; IR(KBr) 3382, 1654 cm⁻¹ ; Anal. Calc. for C₈ H₈ FNO: C, 62.74; H, 5.27; N, 9.15; F, 12.40. Found: C, 62.66; H, 5.17; N, 9.12; F, 12.28.

Part B: 3-Fluoro-4-methylbenzonitrile

A solution of trichloroacetyl chloride (7.3 mL, 65 mmol) in CH₂ Cl₂ (20 mL) was added dropwise over 0.5 h to a solution/suspension of the Part A amide (9.0 g, 59 mmol) and Et₃ N (17 mL, 120 mmol) in CH₂ Cl₂ (80 mL) at 0° C. After 40 min, the mixture was concentrated in vacuo, then diluted with Et₂ O. This solution was extracted with 1 M HCl, sat. aq. NaHCO₃, H₂ O, and brine, then dried (MgSO₄), and concentrated to yield 7.8 g of a tan solid; mp 45-47° C.; IR(KBr) 2232 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 135.0484. Found: 135.0482.

Part C: 2-Fluoro-4-cyanobenzylbromide

N-Bromosuccinimide (9.6 g, 54 mmol) and the part B substrate (7.3 g, 54 mmol) were heated under reflux in CCl₄ (100 mL) under N₂ with irradiation with a high intensity visible lamp for 2 h. After cooling to ambient temp., the mixture was filtered through a Celite pad and concentrated in vacuo. The crude product was recrystallized from hot cyclohexane (4x) to yield 4.5 g of off-white needles; mp 75-77° C.; IR(KBr) 2236 cm⁻¹. RMS, e/z Calc. for (M+H)⁺ : 213.9668. Found: 213.9660.

Part D: 2-Fluoro-4-cyanobenzaldehyde

The part C benzyl bromide (3.68 g, 17 mmol), trimethylamine N-oxide dihydrate (7.6 g, 68 mmol), CH₂ Cl₂ (15 mL), and DMSO (30 mL) were stirred at 0° C. for a few h, slowly warming to ambient T overnight. The mixture was diluted with water (30 mL) and brine (30 mL), and extracted with Et₂ O (4x). The combined organics were washed with brine, dried (MgSO₄), and concentrated to yield 1.1 g of a yellow solid; IR(KBr) 2238, 1706 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 150.0355. Found: 150.0341.

Part E: 2-Fluoro-4-cyanobenzaldoxime

The part D aldehyde (1.1 g, 7.4 mmol), hydroxylamine hydrochloride (1.0 g, 15 mmol), K₂ CO₃ (1.0 g, 7.4 mmol), water (1 mL), and MeOH (10 mL) were heated under reflux for 2.25 h. After brief cooling, the mixture was diluted with water, and the insoluble product was collected by filtration, then rinsed with more water. Drying under high vacuum provided 0.94 g of a pale yellow amorphous solid; mp 179-182° C.; IR(KBr) 3256, 2236, 1556 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 165.0464. Found: 165.0455.

Part F: Methyl 3-(4-cyano-2-fluorophenyl)isoxazolin-5-ylacetate

The part E oxime was allowed to react with Clorox and methyl vinylacetate in the usual way to afford the isoxazoline as a yellow solid in 32% yield; mp 92-94° C.; IR(KBr) 2240, 1746 cm⁻¹ ; HRMS, e/z Calc. for (M+H)⁺ : 263.0832. Found: 263.0818. Anal. Calc. for C₁₃ H₁₁ FN₂ O₃ : C, 59.54; H, 4.23; N, 10.68; F, 7.24. Found: C, 59.84; H, 4.31; N, 10.53; F, 7.26.

Part G: Methyl N² -(m-toluenesulfonyl)-N³ -[3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate.

The part F intermediate was converted to the title compound by the usual sequence of steps: Pinner amidine synthesis, amidine BOC protection, ester saponification, and condensation with the 2,3-diaminopropionate sulfonamide ester; MS (DCI, NH₃) 620 (M+H), 520.

Part H: Methyl N² -(m-toluenesulfonyl)-N³ -[3- (4-amidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminoeropionate hydrochloric acid salt.

The BOC group was removed from the part G intermediate by treatment with 4M HCl in dioxane to provide a yellow gum; HRMS, e/z Calc. for (M+H)⁺ : 520.1666. Found: 520.1675.

EXAMPLE 512A N² -(m-Toluenesulfonyl)-N³ -[3- (4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(S)-2,3-diaminopropionate Hydrochloric Acid Salt

Part A: N² -(m-Toluenesulfonyl)-N³ -[3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate.

The intermediate from Example 512, Part G (0.60 g, 0.97 mmol) was saponified using lithium hydroxide hydrate (61 mg, 1.45 mmol) in water (1 mL) and methanol (1 mL) at room temperature for 3 d. The mixture was extracted with ethyl acetate, the aqueous layer was acidified with pH 4 buffer, and it was extracted with ethyl acetate. The extracts were dried and concentrated to 0.427 g of a clear glass. This material was flashed chromatographed using a methanol/chloroform gradient solvent system, starting with chloroform and progressing through 2%, 10%, 15%, and 20% methanol/chloroform to give 0.360 g (57%) of a clear glass. ¹ H NMR (DMSO-d₆, 300 MHz) δ 9.09 (br, 1H), 7.88-7.80 (m, 3H), 7.60-7.56 (m, 2H), 7.47-7.42 (m, 2H), 5.00-4.97 (m, 1H), 3.62-3.57 (m, 1H), 3.29-3.16 (m, 4H), 2.58-2.43 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H). HRMS (FAB, glycerol) Calc. for (M+H)⁺ : 606.2034. Found: 606.2043.

Part B: N² -(m-Toluenesulfonyl)-N³ -[3-(4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(S)-2,3-diaminopropionate hydrochloric acid salt.

The intermediate from Part A (0.344 g, 0.57 mmol) was dissolved in 4M HCl in dioxane and stirred at room temperature for 21.5 h. The solution was diluted with ether and the precipitated white solid was collected and dried, yielding 0.367 g. This material was subjected to super critical fluid chiral Prep HPLC on a Chiral OG 2 in×25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as eluent at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was obtained as a white solid. ¹ H NMR (DMSO-d₆, 300 MHz) δ 12.81 (br, 1H), 9.53 (s, 1.5H), 9.29 (s, 1.5H), 8.17 (m, 2H), 7.95 (t, J=7.7 Hz, 1H), 7.86 (d, J=12.0 Hz, 1H), 7.40 (d, J=9.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.46-7.41 (m, 2H), 4.97-4.93 (m, 1H), 3.88-3.86 (m, 1H), 3.59-3.55 (m, 1H), 3.42-3.14 (m, 3H), 2.52-2.45 (m, 1H), 2.41-2.33 (m, 4H). HRMS (FAB, glycerol) Calc. for (M+H)⁺ : 506.1510. Found: 506.1494.

EXAMPLE 513 Methyl N² -(n-butyloxycarbonyl)-N³ -[3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt

Prepared using methods described in Ex. 514 to provide a pale yellow powder; mp 90-110° C. (dec); HRMS, e/z Calc. for (M+H)⁺ : 449.2149. Found: 449.2140.

EXAMPLE 514 Methyl N² -(m-toluenesulfonyl)-N³ -[3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt

Part A: 3-cyano-6-pyridaldoxime

5-Cyano-2-picoline (25 g, 0.21 mol) and I₂ were heated under reflux in DMSO (200 mL) for 1 h. After cooling to RT, hydroxylamine hydrochloride (16 g, 0.23 mol), K₂ CO₃ (29 g, 0.21 mol), and water (21 mL) were added. The resulting mixture was heated to 80° C. for 2.5 h, cooled, diluted with water (100 mL) and much acetone, and absorbed onto silica gel by concentration. Chromatography on silica gel, eluting with 0% to 50% EtOAc in hexane, afforded 12.2 g of a tan solid; mp 204-207° C. (dec); HRMS, e/z Calc. for (M+H)⁺ : 148.0511. Found: 148.0516.

Part B: Methyl 3-(3-cyanoeyrid-6-yl)isoxazolin-5-ylacetate

The oxime of Ex. 514, part A was converted to the isoxazoline as described in Ex. 516, part B in 76% yield as a yellow solid; mp 97-98° C.; HRMS, e/z Calc. for (M+H)⁺ : 246.0879. Found: 246.0881. Anal. Calc. for C₁₂ H₁₁ N₃ O₃ : C, 58.77; H, 4.52; N, 17.13. Found: C, 58.74; H, 4.51; N, 17.11.

Part C: Methyl 3-(3-t-butyloxycarbonylamidinoyrid-6-yl)isoxazolin-5-ylacetate

The nitrile of Ex. 514, part B was converted to the amidine as described in the method of Ex. 516, parts D & E (except that 0.6 eq. NaOMe was required), and BOC protected in standard fashion to afford, after purification, a yellow solid; mp 143° C. (gas evolves); HRMS, efz Calc. for (M+H)⁺ : 363.1668. Found: 363.1675. Anal. Calc. for C₁₇ H₂₂ N₄ O₅ : C, 56.35; H, 6.12; N, 15.46. Found: C, 56.35; H, 6.10; N, 15.39.

Part D: Lithium 3-(3-t-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-5-ylacetate

The ester of Ex. 514, part C was saponified and lyophilized as described in the method of Ex. 516, part F to give a colorless amorphous solid quantitatively; mp >230° C.; HRMS, e/z Calc. for conjugate acid (M+H)⁺ : 349.1512. Found: 349.1527.

Part E: Methyl N² -(m-toluenesulfonyl)-N³ -[3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate.

The Part D lithium carboxylate was condensed with methyl N² -(m-toluenesulfonyl)-(S)-2,3-diaminopropionate hydrochloride using conditions described above to give a yellow foam. HRMS, e/z Calc for (M+H)⁺ : 603.2237. Found: 603.2223.

Part F: Methyl N² -(m-toluenesulfonyl)-N³ -[3-(3-amidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate hydrochloric acid salt.

The protected amidine of Part E was treated with 4M HCl in dioxane to provide a yellow solid; mp 90° C. (dec); HRMS, e/z Calc. for (M+H)⁺ : 503.1713. Found: 503.1718.

EXAMPLE 514A N² -(m-Toluenesulfonyl)-N³ -[3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl]-(S)-2,3-diaminopropionic Acid Trifluoroacetic Acid Salt

Part A: Lithium N² -(m-toluenesulfonyl)-N³ -[3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate.

The methyl ester of Example 514, Part E (0.16 g, 0.27 mmol) was saponified by stirring with 0.5 M LiOH (0.54 mL, 0.27 mmol) in methanol (2 mL) at room temperature. The mixture was concentrated in vacuo to give 0.16 g (99%) of a tan solid; HRMS, e/z Calc for (M+H)⁺ : 589.2081. Found: 589.2086.

Part B: N² -(m-Toluenesulfonyl)-N³ -[3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl]-(S)-2,3-diaminopropionic acid trifluoroacetic acid salt.

The lithium salt of Part A was treated with 4M HCl in dioxane to give a tan foam. This material was purified by Prep reverse phase HPLC on a Vydac C18 2×25 cm column using a gradient solvent system starting with 0.05% TFA in water progressing to 80:20 0.05% TFA in water: 0.05% TFA in acetonitrile over 50 m, the purified material was subjected to super critical fluid Prep chiral HPLC on a Chiral OG 2 in×25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as elutant at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was resubmitted to reverse phase Prep HPLC as above to give the title compound as a tan solid. ¹ H NMR (DMSO-d₆, 300 MHz) δ 2.31 (dd, J=15.0, 7.0 Hz, 1H, partially obscured), 2.37 (s, 3H), 2.48-2.59 (m, 1H, under DMSO), 3.02-3.15 (m, 1H), 3.22 (dd, J=17.6, 10.6 Hz, 1H), 3.32-3.42 (m, 1H, under water peak), 3.55 (dd, J=17.6, 10.6 Hz, 1H), 3.82-3.92 (m, 1H), 4.98-5.11 (m, 1H), 7.39-7.49 (m, 2H), 7.54-7.61 (m, 2H), 8.08-8.15 (m, 3H), 8.25 (dd, J=8.4, 2.2 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 9.24 (br s, 2H), 9.53 (br s, 2H), 12.78 (very br s, 1H). MS (ESI) 489 (M+H, 65), 288 (100), 245 (27).

EXAMPLE 515 Methyl N² -(n-butyloxycarbonyl)-N³ -[3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt

In similar fashion to the method described in Ex. 516, the compound of Ex. 514, part E was coupled with methyl N² -(n-butyloxycarbonyl)-2,3-diaminopropionate hydrochloride using-conditions described above, followed by BOC deprotection with 4 M HCl/dioxane to yield a pale yellow powder; HRMS, e/z Calc. for (M+H)⁺ : 449.2149. Found: 449.2154.

EXAMPLE 516 Methyl N² -(m-toluenesulfonyl)-N³ -[3- (2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt

Part A: 2-Chloro-5-pyridaldoxime

2-Chloro-5-formylpyridine (2.1 g, 15 mmol) was condensed with hydroxylamine hydrochloride in the usual way to give the oxime, 1.5 g, as a yellow crystalline solid; mp 171-175° C. (dec); HRMS, e/z Calc. for (M+H)⁺ : 157.0169. Found: 157.0175.

Part B: Methyl 3-(2-chloropyrid-5-yl)isoxazolin-5-ylacetate

Sodium hypochlorite (5% wt, 20 mL) was added dropwise over 1.75 h to a mixture of the part A oxime (1.13 g, 7.2 mmol), methyl vinylacetate (70% purity, 3.0 g, 21 mmol), CH₂ Cl₂ (40 mL), and DMF (4 mL) with stirring at ambient temperature. The CH₂ Cl₂ was evaporated, and the mixture was diluted with EtOAc, extracted with water (5x) and brine, then dried (MgSO₄), filtered, and concentrated. Chromatography on silica gel, eluting with 0% to 70% EtOAc in hexane, afforded 1.4 g of a solid; mp 94-96° C.; HRMS, e/z Calc. for (M+H)⁺ : 255.0536. Found: 255.0531.

Part C: Methyl 3-(2-cyanopyrid-5-yl)isoxazolin-5-ylacetate

The part B chloropyridine (0.51 g, 2.0 mmol), zinc cyanide (0.23 g, 2.0 imol), Pd(PPh₃)₄ (0.12 g, 0.10 mmol), and DMF (2 mL) were heated to 80° C. under N₂ for 3 days. After cooling and concentration, the mixture was preabsorbed onto silica gel by concentration from CHCl₃. Chromatography on silica gel, eluting with 0% to 90% EtOAc in hexane afforded 0.28 g of a pale yellow solid; mp 115-116° C.; HRMS, e/z Calc. for (M+H)⁺ : 246.0879. Found: 246.0880. Anal. Calc. for C₁₂ H₁₁ N₃ O₃ : C, 58.77; H, 4.52; N, 17.13. Found: C, 58.68; H, 4.48; N, 16.90.

Part D: Methyl 3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetate formic acid salt

The part C cyanopyridine (0.47 g, 1.9 mmol) and sodium methoxide (prepared in situ from Na metal, 4 mg, 0.2 mmol were stirred in dry MeOH (6 mL) at ambient temperature for 16 h, after which ¹ H NMR analysis of a reaction aliquot indicated complete formation of methyl imidate [note 9.25 (s, 1H) and 3.92 (s, 3H)]. Ammonium formate (0.60 g, 9.5 mmol) was added to the reaction mixture, and stirring continued for 7 h. The mixture was absorbed onto silica gel by concentration in vacuo. Chromatography on silica gel, eluting with 0% to 20% MeOH in CHCl₃, and concentration afforded 0.61 g of the amidine as an off-white solid; mp 180-182° C. (dec); HRMS, e/z Calc. for (M+H)⁺ : 263.1144. Found: 263.1148.

Part E: Methyl 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate

The part D amidine was BOC protected in standard fashion to afford, after silica gel chromatographic purification, a 41% yield of a colorless foam; HRMS, e/z Calc. for (M+H)⁺ : 363.1668. Found: 363.1682.

Part F: Lithium 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate

The part E methyl ester (0.37 g, 1.0 mmol) was saponified by stirring with 0.5 M LiOH in MeOH at RT. The MeOH was removed in vacua, then the aqueous mixture was frozen and lyophilized to produce a pale yellow solid quantitatively; HRMS, e/z Calc. for conjugate acid (M+H)⁺ : 349.1512. Found: 349.1531.

Part G: Methyl N² -(m-toluenesulfonyl)-N³ -[3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate hydrochloric acid salt

The part F lithium carboxylate was condensed with methyl N² -(m-toluenesulfonyl)-2,3-diaminopropionate hydrochloride using conditions described above, followed by standard BOC deprotection with 4 M HCl/dioxane to yield a yellow amorphous solid; HRMS, e/z Calc. for (M+H)⁺ : 503.1713. Found: 503.1707.

EXAMPLE 516A N² -(m-Toluenesulfonyl)-N³ -[3-(2-amidinopyrid-5-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionic Acid Trifluoroacetic Acid Salt

The methyl ester of Example 516, Part G (31.4 mg, 54.6 nmol) was dissolved in 6M aqueous hydrochloric acid (1 mL) and the mixture was stirred at room temperature for 44 h. The yellow solution was concentrated and subjected to Prep reverse phase HPLC as described in Example 514A, Part B to give 25.0 mg (75%) of a white solid. mp 158.5-161.5° C. ¹ H NMR (DMSO-d₆, 300 MHz) δ 2.31-2.44 (m, 1H), 2.37, 2.38 (singlets, 3H), 2.50-2.60 (m, 1H, under DMSO), 3.00-3.10 (m, 0.5H), 3.12-3.36 (m, 2H), 3.38-3.48 (m, 0.5H), 3.60 (ddd, J=17.2, 10.6, 5.9 Hz, 1H), 3.85-3.95 (m, 1H), 4.95-5.11 (m, 1H), 7.39-7.45 (m, 2H), 7.52-7.60 (m, 2H), 8.10-8.22 (m, 2H), 8.28-8.40 (m, 2H), 9.06 (s, 1H), 9.37 (br s, 2H), 9.60 (br s, 2H). MS (ESI) 489 (M+H, free base, 100), 214 (17).

EXAMPLE 528a N² -o-Bromophenylcarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid

The title compound was obtained as its TFA salt from readily accessible N² -amino-3-[(4-tertbutyloxycarbonylamidino)phenylisoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diamino-tertbutylpropionate by common acylation techniques with 2-bromobenzoyl chloride. Removal of the tert-butyl protecting groups with TFA afforded the desired product as colorless crystals. M.P. 172-174° C.; ¹ H NMR (DMSO d6) δ: 7.80(d, J=8Hz, 2H), 7.51-7.63(m, 3H), 7.28 (m, 2H), 7.12 (dd, 1H), 6.61 (m, 1H), 5.05 (m, 1H), 4.81(q, 1H), 3.80 (d, 3H), 3.06 (m, 1H), 2.53 (m, 2H), 1.53 (s, 9H)ppm; ESI mass spectrum 516(M+H, 100 free base); HRMS calcd. for C₂₂ H₂₃ BrN₅ O₅ 516.088255, found 516.086811 (free base).

EXAMPLE 536 N² -(2,5-Dimethyl-4-chlorobenzenesulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 536 (M+H)⁺, (100%).

EXAMPLE 540 N² -methylphenylcarbonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid

Obtained as colorless crystals, M.P. 166-168° C.; ¹ H NMR (DMSO d6) δ: 9.38 (b, 2H), 9.18 (b, 2H), 8.42 (t, 1H), 8.20 (m, 1H), 7.21 (d, J=10.2 Hz, 4H), 5.00 (m, 1H), 4.50 (m, 1H), 3.30-3.73 (m. 3H), 2.58-2.65 (dd, 1H), 2.41-2.50 (dd, 1H), 2.34 (s, 3H)ppm; ESI mass spectrum 452(M+H, 100 free base); HRMS calcd for C₂₃ H₂₆ N₅ O₅ 452.193394, found 452.1922251(free base).

EXAMPLE 540a N² -methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid

Obtained as colorless crystals M.P. 136-138° C.; ¹ H NMR (DMSO d₆) δ: 9.39 (b, 2H), 9.27 (s, 2H), 8.18 (m, 2H), 7.80 (d, J=7.7 Hz, 1H), 7.44(t, 1H), 7.32(q, 2H), 4.96 (m, 1H), 3.90 (b, 1H), 3.81 (q, 1H), 3.40-3.60 (m, 2H), 3.04 (m, 2H), 2.60 (s, 2H), 2.24 (dd, J=7.7 and 15.6 Hz)ppm; ESI mass spectrum 488(M+H, 100 free base). HRMS calcd for. C₂₂ H₂₅ N₅ SO₆ 488.160381, found 488.16292 (free base).

EXAMPLE 548 Preparation of 3-bromothiophene-2-sulfonyl Chloride

A solution of chlorosulfonic acid (14.3 g, 0.12 mol) in 35 mL of 1,2-dichloroethane was chilled to -10° C. and protected from moisture. Phosphorus pentachloride (20.8 g, 0.1 mol) was added in small portions while maintaining the temperature between -5° and -10° C. The resulting slurry was stirred at -10° C. for 30 minutes. Then, 3-bromothiophene (16.3 g, 0.1 mol) was added dropwise over a period of 45 minutes, maintaining the temperature between -5° and +5° C. During the addition of the 3-bromothiophene, hydrogen chloride gas was evolved; the reaction mixture became thick and pasty, and difficult to stir. Upon complete addition of the 3-bromothiophene, the reaction temperature was held at 0° C. for two hours. The reaction was then heated to 80° C. and kept there for one hour; during which the solids dissolved, and hydrogen chloride gas was evolved once more. The reaction mixture was chilled in an ice bath, poured over 250 g crushed ice, and stirred for one hour as the ice melted. The resulting two phase system was separated and the aqueous layer washed three times with 125 mL of chloroform. The combined organic phases were dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give 24.1 g (92%) of crude product as a dark amber oil; ¹ H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=5.3, 1H), 7.73 (d, J=5.3, 1H); Mass Spectrum (CH₄ -DCI/GC-MS, e/z, relative abundance) 262.8, (M+H)⁺, 100%; 226.9, (M+H-HCl)⁺, 89.7%.

EXAMPLE 587A N² -3-methylphenylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionic Acid

The compound of Example 473C, Part B (0.077 g, 0.14 mmol) was dissolved in MeOH (4 ml), LiOH (0.0066 g, 0.158 mmol) in H₂ O (4 ml) was added and the reaction mixture left to stir overnight. After evaporation of methanol the product precipitated from the aqueous as a white solid (0.027 g, 35% yield). HRMS calc'd for C₂₂ H₂₅ N₅ O₆ S: 488.160381 found: 488.160827.

EXAMPLE 602 Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-guanidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt

Part A: [3-[(4-t-butyloxycarbonylamino)phenyl]-isoxazolin-5-yl]acetic acid: This compound was prepared in 49% yield from 4-t-butyloxycarbonylaminobenzaldoxime and t-butyl vinyl acetate using the procedure described above for Ex. 275, Part A. ¹ HNMR(CDCl₃) δ 0.99 (t, 3H), 1.35 (m, 2H), 1.50 (s, 9H), 1.61 (m, 2H), 2.60 (dd, J=7.7 and 16.5 Hz, 1H) 2.84 (dd, J=5.9 & 16 Hz, 1H), 3.06 (dd, J=7.4 & 16.9 Hz, 1H), 3.48 (dd, J=10.3 & 16.5 Hz, 1H), 4.10 (t, 2H), 5.03 (m, 1H), 6.60 (broad s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.58 (J=8.3 Hz, 2H); IR(KBr): 2966, 1734, 1740, 1610, 1578, 1528, 1508, 1458, 1442, 1412, 1392, 1368 1234, 1160, 1058, 916, 878, 828, 772, 612 cm⁻¹ ; HRMS calcd. for C₂₀ H₂₈ N₂ O₅ : 377.207647, Found 377.207278. Standard LiOH saponification conditions then afforded the corresponding carboxylic acid compound as colorless crystals in 88% yield. mp 178-180° C.; ¹ HNMR(CDCl₃) δ 1.52 (s, 9H), 2.67 (dd, J=7.8 and 16 Hz, 1H), 2.89 (dd, J=8.3 & 16 Hz, 1H), 3.06 (dd, J=9.5 & 16.9 Hz, 1H), 3.48 (dd, J=10.3 & 16.5 z, 1H), 5.03(m, 1H).

Part B: Methyl N² -n-butyloxycarbonyl-N³ -[3-[(4-t-butyloxycarbonylamino)phenyl]isoxazolin-5-yl acetyl]-(S)-2,3-diaminopropionate: The compound of Example 602, Part A was condensed with methyl N² -tBoc-(S)-2,3-diaminopropionate using the procedure described for Ex. 275, Part C above to provide the desired product. mp 80-82° C.; ¹ HNMR(CDCl₃) δ 1.88 (t,3H), 1.30 (m,2H), 1.47 (sm, 20H), 2.50 (dd, 1H), 2.61 (dd, 1H), 3.07 (dd, 1H), 3.40 (dd, 1H), 3.63 (t, 2H), 3.74 (s, 3H), 4.00 (m, 2H), 4.38 (m, 1H), 5.00 (m, 1H), 5.88 (dd, 1H), 6.77 (t, 1H), 7.58 (d, 2H), 7.84 (d, 2H), 10.4 (s, 1H), 11.6 (s, 1H); IR(KBr):3286, 2964, 1722, 1646, 1546, 1414, 1368, 1340, 1312, 1294, 1240, 1156, 1122, 1100, 1058, 1030, 844, 776 cm⁻¹. Mass spectrum (CI/NH₄) 663 (M+H, 20),563(7), 549(78), 506(81),463(100).

Part C: Methyl N² -n-butyloxycarbonyl-N³ -(3-(4-quanidinophenyl)isoxazolin-5-yl acetyl]-(S)-2,3-diaminopropionate: The compound of Ex 602, part B was treated with TFA in dichloromethane to afford the corresponding aniline as its TFA salt. This intermediate was converted to the corresponding bis-BOC protected quanidino compound in 59% yield using the method of Kim et al. (Tet. Lett. 1993, 48, 7677). Deprotection under standard conditions (TFA/CH₂ Cl₂) provided the title compound as its TFA salt (90%). ¹ HNMR(DMSO-d₆) δ 1.89 (t, 3H), 1.34 (m, 2H), 1.57 (m, 2H), 2.44 (dd, 1H), 2.58 (t, 2H), 2.64 (m, 1H), 3.17 (m, 1H), 3.40 (m,2H), 3.65 (m, 1H), 3.70 (s, 3H), 4.00 (t, 2H), 4.31 (m, 1H), 5.02 (m, 1H), 6.80 (m, 1H), 7.28 (d, 2H), 7.64 (broads, 3H), 7.68 (d, 2H), 7.84 (broad, 1H) ; Mass spectrum(ES) m/z 463 (M+H, 100).

EXAMPLE 606 Methyl N² -p-toluylsulfonyl-N³ -[3-(4-quanidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: The methyl di-Boc-quanidino-α-toluyl ester was prepared according to the procedure for example 602. Deprotection of the Boc-protecting groups then afforded example 606 as the TFA salt. ¹ HNMR (DMSO) δ: 8.30 (dd, 2H), 8.09 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 4.88 (m, 1H), 4.00 (m, 1H), 3.42 (dt, 1H), 3.38 ((d, 3H), 3.05-3.33 (m, 3H), 2.40 (m, 1H), 2.36 (s, 3H), 2.25 (m, 1H) ppm; HR MS calcd. for C₂₃ H₂₉ N₆ O₆ S 517.186930; Found 517.186911.

Part B: Lithium hydroxide saponification on the product of part A then afforded example 605 in 39% yield after recrystallization from dichloromethane and ether. 1HNMR (CD₃ OD) δ: 8.29(brd, S, 2H), 8.05 (brd, s, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.31 (d, 4H), 5.02 (m, 1H), 3.85 (m, 1H), 3.60 (m, 2H), 3.41 (m, 1H), 3.20 (m, 1H), 2.64 (dd, 1H), 2.43 (dd, 1H), 2.40 (s, 3H);HR MS calcd. for C₂₂ H₂₇ N₆ O₆ S 503.171280; Found 503.170531.

EXAMPLE 625 N² -p-methylphenylsulfonyl-N³ -[3- (4-amidinophenylmethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: 1-β-nitroethene-4-benzonitrile (Bourgvignon, J.et al., Can, J. Chem., 1985, 63, 2354) (0.9 g, 5.17 mmol) was reduced according to the method of Nakamura, et al. (Chem. Lett., 1985, 523) to afford 0.73 g (80%) of desired product. ¹ H NMR (CDCl₃) δ: 7.73 (d, J=8.42 Hz, 2H), 7.43 (d, J=8.42 Hz, 2H), 4.75 (d, J=6.96 Hz, 2H), 3.48 (d, J=6.96 Hz, 2H) ppm; Mass Spectrum (CH₄ -CI) m/z (M+H)⁺ 177 (100%).

Part B: 1-β-nitroethane-4-benzonitrile (1.38 g, 7.8 mmol) was condensed with tert-butyl acrylate (1.4 ml, 9.4 mmol) according to the method of Curran, D. P., et al (J. Org. Chem., 1988, 53, 5369) to afford the crude ester. The ester was difficult to purify so the ester was hydrolyzed in 30 ml of 30% TFA/CH₂ Cl₂ for 48 h. The crude acid was extracted into aqueous NaHCO₃. The aqueous layer was acidified and extracted with CH₂ Cl₂ and dried (MgSO₄) to afford 1.48 g (80%) orange solid. ¹ H NMR (CDCl₃) δ: 7.97 (brd, 1H), 7.64 (d, J=8.42 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 5.07 (dd, J=6.59,10.98 Hz, 1H), 3.79 (s, 2H), 3.20 (m,. 2H) ppm.

Part C: The product of Part B (366 mg, 1.6 mmol) was coupled with methyl-L-N.sup.α -p-toluylsulfonyl-2,3-diaminoproprionate using procedure described in Example 43D. Chromatography on silica gel (2%MeOH/CH₂ Cl₂) afforded 388 mg (50%).mp 141-144° C; ¹ H NMR (CDCl₃) δ: 7.75-7.65 (m, 2H), 7.60 (d, 2H), 7.45 (d, 2H), 7.30 (dd, 2H), 7.20 (m, 1H), 5.50 (dd, 1H), 4.99 (m, 1H), 4.20-3.99 (m, 1H), 3.90-3.70 (m, 3H), 3.55 (s, 3H), 3.30 (m, 3H), 2.42 (s, 3H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+H)⁺ 485.2 (100%); IR (KBr) 3276, 1738, 1666, 1538, 1338, 1162, 862, 822 cm⁻¹.

Part D: The product of Part C (360 mg, 0.74 mmol) was subjected to the Pinner reaction previously described. Chromatography on silica gel (5-15% MeOH/CH₂ Cl₂) afforded 313 mg (75%) .mp 133-137° C.; ¹ H NMR (DMSO-d₆) δ: 9.20 (brd, 2H), 8.26 (t, J=5.86 Hz, 1H), 7.80 (d, J=8.06 Hz, 2H), 7.63 (d, J=8.06 Hz, 2H), 7.51 (d, J=8.06 Hz, 2H), 7.38 (d, J=8.06 Hz, 2H), 4.87-4.73 (m, 1H), 3.98-3.89 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 3.34-3.31 (m, 3H), 3.28 (m, 2H), 2.98 (dd, J=6.23, 17.21 Hz, 1H), 2.37 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 502.2 (100%).

Part E: To the product of Part D (182 mg, 0.338 mmol) was added 1 ml MeOH, followed by lithium hydroxide (31 mg, 0.74 mmol). The mix ture was stirred for 18 h and the solvent was removed in vacuo and water added. HCl was added until a precipitate formed. The solid was filtered off and stirred in 2 ml HCl for 1 h. The acid was removed in vacuo to afford 72 mg of product which contained 15% methyl ester. Purification via standard HPLC techniques then afforded the desire product. ¹ H NMR (DMSO-d₆) δ: 9.35 (s, 2H), 9.08 (s, 2H), 8.14-8.07 (m, 2H), 7.78 (d, J=7.32 Hz, 2H), 7.66 (dd, J=2.19, 8.42 Hz, 2H), 7.51 (d, J=7.69 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 4.86-4.69 (m, 1H), 3.92-3.80 (m, 1H), 3.79 (s, 2H), 3.30-2.90 (m, 4H), 2.49 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)+488.3 (100%).

EXAMPLE 651 Methy N² -benzyloxycarbonyl-N³ -methyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt

Part A. Preparation of methyl N² -benzyloxycarbonyl-N³ -methyl-[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate.

To a mixture of 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (prepared according to the procedure of Example 434, part F; 189 mg, 0.54 mmol), methyl N³ -methyl-N² -Cbz-L-2,3-diaminopropionate (prepared according to Sakai and Ohfune, J. Am. Chem. Soc. 114, 998 (1992); 145 mg, 0.54 mmol) and TBTU (175 mg, 0.54 mmol) in ethyl acetate (10 mL) was added triethylamine (0.15 mL, 1.09 mmol). After stirring for 26 h, the mixture was diluted with ethyl acetate, washed with pH 4 buffer, then with saturated aqueous sodium bicarbonate, then with saturated brine. The organic phase was dried (MgSO₄) and concentrated. The residue was flash chromatographed (ethyl acetate) to provide the product as a colorless glass (279 mg, 86%): NMR (CDCl₃) δ 7.88 (m, 2H), 7.69 (m, 2H), 5.79 (bd, 1H), 5.09 (m, 3H), 4.58 (m, 1H), 3.86 (m, 1H), 3.77 (2s, 3H), 3.63 (m, 2H), 3.14 (dd, 1H), 3.01 (2s, 3H), 2.9 (m, 1H), 2.53 (m, 1H), 1.66 (b, 2H), 1.56 (s, 9H); mass spec (ESI) m/z 596.2 (M+H⁺, 100%).

Part B. Preparation of Methyl N² -benzyloxycarbonyl-N³ -methyl-N³ -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part A (226 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (1 mL). After stirring at room temperature for 4 h, the mixture was diluted with ether and stirred. The resulting white solid was collected by filtration to provide the title product as a white solid (201 mg, 87%): NMR (DMSO-d₆) δ 9.39 (bs, 2H), 9.19 (bs, 2H), 7.87 (s, 4H), 7.79 (t, 1H), 7.32 (m, 5H), 5.03 (3H), 4.40 (m, 2H), 3.90 (m, 1H), 3.65 (2s, 3H), 2.95 and 2.82 (4s, 3H), 3.6-2.8 (4H); mass spec (ESI) m/z 496.3 (M+H⁺, 100%).

EXAMPLE 666 N² -(methyl)-N² -m-toluylsulfonyl-N³ [-3-(4-amidinophenyl)-isoxazoline-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: Methyl N³ -[3-(4-cyanophenyl)isoxazolin-5-(R,S)-ylacetyl]-N² -m-toluyl-(S)-2,3-diaminopropionate obtained as the precursor to Example 300 was subjected to a selective Mitsonubo-N-methylation of the sulfonamide (Acta. chem. scand. 1994, 48, 324333),to afford methyl N² -(methyl)-N² -m-toluyl-N³ -[3-(4-cyanophenyl)isoaxzolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate as colorless crystals. M.P=148-149° C. ¹ HNMR(CDCl₃) δ: 7.77 (d, 2H), 7.60 (m, 2H), 7.46 (m, 2H), 7.41 (d, 2H), 6.07 (t, 1H), 5.21 (m, 1H), 4.80 (dd, J=4.8 & 10.6 Hz, 1H), 3.81 (m, 1H), 3.56 (s, 3H), 3.43 (m, 2H), 3.25 (dd, J=7.4 & 17.4 Hz, 1H), 2.80 (dd, J=8 & 17.1 Hz, 1H), 2.77 (s, 3H), 2.56 (dd, J=7.7 & 15.1 Hz, 1H), 2.44 (s, 1H) ppm; IR (KBr) 3340, 2224, 1726, 1644, 1610, 1596, 1534, 1440, 1414, 1402, 1366, 1336, 1284, 1258, 1212, 1144, 1012, 934, 918, 896, 844, 812, 784, 690, cm⁻¹. ESI mass spectrum 499 (M+H, 48), 359(63), 279(53), 198(100). HR MS calcd. for C₂₄ H₂₇ N₄ O₆ S 499.165132 found 499.164946.

Part B: The cyano procursor from part A was then subjected to the Pinner amidine reaction conditions as per example 275E to obtain the desired compound as the methyl ester in 60% overall yield. Saponification with 6N HCl followed by HPLC purification [solvent A: CH₃ CN: H₂ O: TFA/2%:98%:0.05%, solvent B: CH₃ CN:H₂ O:TFA/80%:20%:0.05%] afforded the desired amidine acid compound 666 as its TFA salt. ¹ HNMR (CDCl₃) δ: 9.35 (s, 1H), 9.23 (s, 1H), 8.20 (brd, 2H), 7.89 (brd, 4H), 7.57 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz, 2H), 5.05 (m, 1H), 4.67 (m, 1H), 3.50-3.66 (m, 3H), 3.20-3.40 (m, 2H), 2.80 (s, 3H), 2.55 (m, 1H), 2.35 (m/s, 4H) ppm; ESI mass spectrum 502(M+H, 100), HRMS calcd for C₂₃ H₂₇ N₅ SO₆ 502.176031 found 502.176612.

EXAMPLE 703 Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazol-5-yl acetyl]-L-2,3-diaminopropionate TFA Salt

Part A. Preparation of Methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate

To a suspension of methyl 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-yl acetate (5.28 g, 21.62 mmol) in chloroform (150 mL) were added N-bromosuccinimide (4.23 g, 23.78 mmol) and AIBN (100 mg) and the mixture was refluxed. Small amounts of AIBN (100 mg-200 mg) were added at one hour intervals until TLC showed a complete reaction. Potassium acetate (17.3 g) and acetic acid (6.5 mL) were added and the reaction mixture was refluxed for 1 hour, cooled, then poured into lN NaOH (325 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined and washed with sat. NaCl, dried over Na₂ SO₄, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 35% EtOAc in Hexane) to yield 2.2 g (42%) of an off-white solid as product; ¹ H NMR (300 MHz, CDCl₃) δ: 7.93 (dd, 2H), 7.76 (dd, 2H), 6.67 (s, 1H), 3.92 (s, 2H), 3.8 (s, 3H).

Part B. Preparation of Methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt.

A suspension of methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate (2.19 g, 9.04 mmol) in 100 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a solution was obtained. The total addition time was two hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 500 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25° C. for 3 hours. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 2.3 g (82%) of the hydrochloride salt; ¹ H NMR (300 MHz, suspension in CDCl₃) δ 8.52 (d, J=8.06 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 6.67 (s, 1H), 4.6 (s, 3H), 3.93 (s, 2H), 3.8 (s, 3H).

Part C. Preparation of Methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt.

A solution of methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt (2.3 g, 7.4 mmol) in 50 mL of anhydrous methanol was chilled in an ice bath and 2M ammonia in methanol (18.5 mL, 37 mmol) was added. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of 24 hrs. The amber solution was then concentrated in vacuo to give 2.2 g (quant. yield) of a yellow foam; ¹ H NMR (300 MHz, d₆ -DMSO) δ 9.6-9.2 (b), 8.12 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 4.15 (s, 2H), 3.7 (s, 3H).

Part D. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate.

To a solution of methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt (2.2 g, 7.4 mmol) in 30 mL DMF cooled with an ice bath was added triethylamine (2.06 mL, 14.8 mmol) and di-tert-butyl dicarbonate (1.78 g, 8.14 mmol). The reaction mixture was warmed to room temperature and stirred for 64 hrs. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was washed with EtOAc. The organic layers were combined and washed with water, sat. NaCl, dried over Na₂ SO₄, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 25% EtOAc in Hexane) to afford 1.45 g (54%) of product; ¹ H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 3.91 (s, 2H), 3.8 (s, 3H), 1.56 (s, 9H).

Part E. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid.

To a solution of methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate (1.45 g, 4.03 mmol) in 30 mL of methanol was added a solution of lithium hydroxide monohydrate (0.195 g, 4.64 mmol) in water (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and the resulting mixture was cooled using an ice bath. 1N HCl was slowly added to a pH of 3-4 and the resulting acidic aqueous mixture was extracted repeatedly with EtOAc. The organic layers were combined and washed with sat. NaCl, dried over Na₂ SO₄, filtered and concentrated in vacuo to yield 0.97 g (70%) of an off-white powdery solid as product; ¹ H NMR (300 MHz, d₆ -DMSO) δ 8.07 (d, J=8.79 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.03 (s, 1H), 3.99 (s, 2H), 1.45 (s, 9H).

Part F. Preparation of Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate.

To a solution of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid (0.262 g, 0.76 mmol), methyl N² -n-butyloxycarbonyl-L-2,3-diaminopropionate HCl salt (0.193 g, 0.76 mmol), and TBTU (0.256 g, 0.8 mmol) in DMF (15 mL) was added triethylamine (0.45 mL, 3.23 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and water. The water layer was washed twice with EtOAc. The organic layers were combined and washed with water, pH 4 buffer, 5% NaHCO₃, and sat. NaCl, dried over Na₂ SO₄, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel (100% EtOAc) to yield 0.315 g (76%) of a slightly amber foam; ¹ H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.42 Hz, 2H), 7.83 (d, J=8.42 Hz, 2H), 6.6 (s, 1H), 6.57 (bm, 1H), 5.66 (bm, 1H), 4.45 (bm, 1H), 4.05 (m, 2H), 3.77 (s, 5H), 3.7 (m, 2H), 1.57 (s, 9H), 1.56 (m, 2H), 1.35 (m, 2H), 0.9 (t, J=7.32 Hz, 3H).

Part G. Preparation of Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate TFA salt.

A solution of methyl N² -n-butyloxycarbonyl-N³ -[3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate (0.215 g, 0.39 mmol) in 1:1 methylene chloride/trifluoroacetic acid (20 mL total) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue chromatographed on silica gel (10% to 30% methanol in chloroform) to yield 0.11 g (50%) of a white solid; ¹ H NMR (300 MHz, d₆ -DMSO) δ 9.4 (bs, 2H), 9.15 (bs, 2H), 8.45 (t, 1H), 8.11 (d, J=8.42 Hz, 2H), 7.94 (d, J=8.42 Hz, 2H), 7.53 (d, J=8.06 Hz, 1H), 7.01 (s, 1H), 4.21 (m, 1H), 3.95 (t, 2H), 3.81 (s, 2H), 3.62 (s, 3H), 3.55 (m, 1H), 3.34 (m, 1H), 1.5 (m, 2H), 1.3 (m, 2H), 0.87 (t, J=7.32 Hz, 3H).; Mass Spectrum (ESI, e/z, relative abundance) 446.3, (M+H)⁺, 100%.

EXAMPLE 717 N² -Phenylmethylsulfonyl-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 488 (M+H)⁺, (100%).

EXAMPLE 816 N² -p-toluylsulfonyl-N³ -[5-(4-amidinophenyl)isoxazolin-3-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

The title compound was prepared in a manner similar to example 829. Saponification of the methyl ester via standard techniques then afforded crude compound 816, which was purified via HPLC [graduant flow, solvent A CH₃ CN(2%):H₂ O(98%):TFA(0.05%), solvent B: CH₃ CN(80%):H₂ O(20%):TFA(0.05%),] to afford colorless crystals of compound 816 as its TFA salt. ¹ HNMR(CDCl₃) δ:

9.30 (brds, 4H), 8.34 (t, 1H), 8.12 (d,J=9.2 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 5.60 (dt, 1H), 3.81 (q, 1H), 3.43 (dt, 1H), 3.25 (m, 1H), 3.20 (d, 1H), 3.03 (m, 1H), 2.89 (m, 1H), 2.50 (s, 1H), 2.34(s,3H) ppm; ESI mass spectrum 488 (M+H,100), HRMS calcd. for C₂₂ H₂₆ N₅ O₆ S 488.160381; found 488.158785.

EXAMPLE 829 Methyl N² -n-butyloxycarbonyl-N³ -[5-(4-amidinophenyl)isoxazolin-3-yl acetyl]-(2S)-2,3-diaminopropionate

Part A: t-Butyl [5-(4-cyanophenyl)isoxazolin-3-yl]acetate:

Cycloaddition of 4-cyanophenylethylene (MP & D chemical Co.) and tert-butyl-3-oxopropionate oxime was carried out following the procedure of Gree et. al. (Bioorganic & Medicinal Chemistry letters 1994, 253) to provide the desired isoxazoline in 72% yield. ¹ HNMR(CDCl₃) δ: 1.40 (s, 9H), 3.00 (dd, J=8.3 and 17 Hz, 1H), 3.35 (dd(AB) J=18 and 8.3 Hz, 2H),3.48 (m, 1H), 5.60 (dd, J=9 and 4.5 Hz, 1H), 7.47 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H); IR 2235, 1718, 1610 cm⁻¹. Mass spectrum m/z 287(M+H, 100).

Part B: [5-(4-cyanophenyl)isoxazolin-3-yl]acetic acid:

Hydrolysis of the compound of Ex.829, Part A with excess TFA in dichloromethane afforded the acid in 90% yield. ¹ HNMR (CDCl₃) δ 3.00 (dd, J=8 and 17.2 Hz, 1H), 3.55 (s, 2H), 3.59 (m, 1H), 5.66 (dd, J=8 and 11 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H); IR(KBr) 3325, 2235, 1718, 1605 cm⁻¹ ; Mass spectrum m/z 231 (M+H, 100).

Part C: Methyl [5- (4-Boc-amidinophenyl)isoxazolin-3-yl]Acetate:

The compound of Ex. 829, Part B compound was then subjected to the standard Pinner reaction conditions described in Ex. 275, Part D to afford an amidino compound, which, without purification, was subjected to treatment with di-tert-butyldicarbonate in dioxane/water (9:1) and excess triethylamine to afford the desired compound in 28% yield. ¹ HNMR(CDCl₃) δ 1.54 (s,9H), 2.98 (dd, J=8 and 17 HZ, 1H), 3.49 (s, 2H), 3.53 (m, 1H), 3.71 (s, 3H), 5.63 (dd, J=8 & 11.4 Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 362(M+H, 8), 306(18), 262(M+H-Boc, 100).

Part D: [5-(4-Boc-amidinophenyl)isoxazolin-3-yl]acetic acid:

Hydrolysis of the ester using standard LiOH conditions afforded the desired acid in 5% yield. ¹ HNMR(CDCl₃) δ 1.54 (s,9H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.51 (s, 2H), 3.53 (m, 1H), 5.63 (dd, J=8 & 11.4 Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 348(M+H,12),248(M+H-Boc, 100).

Part E: Methyl N² -n-butyloxycarbonyl-N³ -[5-(4-amidinophenyl)isoxazolin-3-yl-acetyl](S)-2,3-diaminopropionate, trifluoroacetate:

The compound of Ex. 829, Part D was coupled with methyl-(S)-N² -n-butyloxycarbonyl-2,3-diaminopropionate following the procedure described in Ex. 275, Part C to give the Boc protected intermediate in 80% yield. ¹ HNMR(CDCl₃) δ 0.89 (t, 3H), 1.32 (m, 2H), 1.53 (s, 9H), 1.17 (m, 2H), 2.95 (dd, J=8 and 17 HZ, 1H), 3.33 (s, 2H), 3.46 (m, 1H), 3.60 (m, 2H), 3.73 (s, 3H), 4.00 (m, 2H), 4.31 (m, 1H), 5.60 (dd, J=8 & 11.4 Hz, 1H), 5.70 (bd, 1H), 6.70 (broad, 1H), 7.33 (d, 8.2 Hz, 2H), 7.89 ((d, 8.2 Hz, 2H); Mass spectrum m/z 534 (M+H, 30), 434 (M+H-Boc, 100). Deprotection by treatment of the above Boc-amidine with excess TFA in dichloromethane provided the title compound as the TFA salt. ¹ HNMR(CDCl₃ /DMSO-d₆) δ 1.88 (t, 3H), 1.30 (m, 2H), 1.53 (m, 2H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.32 (s, 2H), 3.40-3.63 (m, 3H), 3.63 (d, 3H), 3.98 (t, 2H), 4.29 (m, 1H), 5.60 (dd, J=8 & 11 Hz, 1H), 6.80 (d, 1H), 7.50 (d, J=8 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 8.03 (broad s, 1H), 9.05 (broad s, 2H); IR(KBr): 3388, 1718, 1664, 1620, 1528, 1456, 1436, 1384, 1366, 1280, 1254, 1168, 1144, 1074, 980, 882, 778 cm⁻¹ ; Mass spectrum(ES) m/z 448 (M+H, 100)

EXAMPLE 952 Methyl N² -m-toluenesulfono-N³ -[3-(4-N-isopropylamidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate

Methyl N² -m-toluenesulfono-N³ -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate (prepared as in example 473 part C above) (0.098 g, 0.0002 mol) was stirred with isopropyl alcohol (0.018 ml, 0.0002 mol) and sulfuric acid (5 ml) for 12 hours. The reaction mixture was poured over ice and diluted to three times its' volume with water. The title compound was filtered as a pale brown solid. ¹ H NMR (CDCl₃) δ: 7.79-7.61 (m, 6H); 7.38-7.36 (m, 2H); 6.49-6.40 (m, 1H); 6.01-5.99 (m, 1H); 5.62-5.55 (m, 1H); 5.19-5.08(m, 1H); 4.31-4.28(m, 1H); 4.11-3.99(m, 1H); 3.56 (s, 3H); 3.72-3.48 (m, 4H); 3.24-3.16 (dd, 1H, J=7.3, 17.0); 2.41 (s, 3H); 1.29-1.27 (d, 6H, J=6.59 Hz). MS(ESI) calc'd for C₂₆ H₃₂ N₄ SO₇ 545.3 found 545.2 (M+H)⁺

EXAMPLE 954 N² -3-(n-butylcarbamoyl)-N³ -[3- (4-amidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionic Acid

Following the procedure outlined for example 1945 above, Methyl N² -3-(n-butylcarbamoyl)-N³ -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate (0.87 g, 0.002 mol) gave a 66% yield of N² -3-(n-butylcarbamoyl)-N³ -[3-(4-amidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionic acid. ¹ H NMR (CDCl3) δ: 12.7 (bs, 1H); 8.12-8.09 and 7.28-7.26 (2m, 1H); 8.05 and 7.43 (2s, 1H); 7.94-7.92 (d, 2H, J=8.54); 7.87 (s, 1H); 7.73-7.70 (d, 2H, J=8.5 Hz); 6.51-6.49 (m, 1H); 5.02-4.95 (m, 1H); 3.95-3.90 (m, 1H); 3.58-3.47 (m, 2H); 3.29-3.13 (m, 2H); 2.72-2.38 (m, 4H); 1.52-1.46 (m, 2H); 1.34-1.25 (m, 2H); 0.87-0.85 (t, 3H, J=4.3 Hz). MS(ESI): Cacl'd for C20H26N407 435.2 found 435.2 (M+H)⁺.

EXAMPLE 956 N² -3-methylphenylsulfonyl-N³ -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionic Acid

Part A: Methyl N² -m-toluenesulfono-N³ -[3-(4-amidophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate hydrochloride.

Methyl N² -m-toluenesulfono-N³ -[3-(4-cyanophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate (0.19 g, 0.00039 mol) was dissolved in 10 ml concentrated sulfuric acid. After stirring for 12 hours the reaction mixture was poured over 10 g of ice and 20 ml of water was added. The white solid was filtered, washed once with water and dried under vacuum overnight to give methyl-N² -m-toluenesulfono-N³ -[3-(4-amidophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate as a white powder. IR(neat) cm⁻¹ : 3404, 3340, 3274, 3202, 2930, 1710, 1652, 1612, 1526, 1320, 1286, 1238, 1174, 1100, 1086, 1070, 886, 850, 614, 574. MS(ESI): calc'd for C₂₃ H₂₆ N₄ O₇ S 503.2 found 503.3(M+H)⁺.

Part B: N² -m-toluenesulfono-N³ -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionic acid

Methyl N² -m-toluenesulfono-N³ -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate hydrochloride (0.146 g, 0.29 mmol) was dissolved in MeOH (5 ml), LiOH (0.013 g, 0.32 mmol) in H₂ O (5 ml) was added and the reaction mixture left to stir overnight. Purification was done by HPLC on a Vyadek column using a gradient of 0.05%TFA/water to 0.05%TFA/acetonitrile over 45 min. The flow was set to 10 ml/min and the detector at 254 nm. The peak eluted at 25 min, the volatiles were evaporated in vacuo, and the solid dried under vacuum. MS(ESI) calc'd for C₂₂ H₂₄ N₄ O₇ S: 489.2 found: 489.2.

EXAMPLE 978 Methyl N² -m-toluenesulfono-N³ -[3-(5-amidopyrid-2-yl)isoxazolin-5S-ylacetyl]-2,3-diaminopropionate

mp 192-195.5° C. (dec). ¹ H NMR (DMSO-d₆, 300 MHz) δ 2.28 (dd, J=14.6, 7.0 Hz, 1H), 2.36 (s, 3H), 2.44-2.54 (m, 1H, under DMSO), 3.04-3.15 (m, 1H), 3.20 (dd, J=17.6, 7.3 Hz, 1H), 3.30-3.40 (m, 1H, under water), 3.53 (dd, J=17.6, 10.6 Hz, 1H), 3.80-3.89 (m, 1H), 4.92-5.05 (m, 1H), 7.38-7.48 (m, 2H), 7.54-7.61 (m, 2H), 7.68 (br s, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.04-8.10 (m, 2H), 8.23 (br s, 1H), 8.27 (dd, J=8.1, 2.2 Hz, 1H), 9.06 (d, J=1.5 Hz, 1H), 12.76 (br s, 1H). IR (KBr) 3388, 3314, 3274, 3186, 1712, 1662, 1584, 1546, 1418, 1344, 1160, 934, 794, 712, 688, 620, 576 cm⁻¹. MS (ESI) 490 (M+H, 100).

EXAMPLE 979 N² -[(p-ethyl)phenylsulfonyl]-N³ -[3-(4-carboxamidophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate

¹ HNMR (DMSO) δ 8.12 (2H,m), 7.94 (2H, d, J=8.423 Hz), 7.74 (2H, m), 7.70 (2H, d, J=8.423 Hz), 7.46 (1H, s),7.40 (2H, m), 4.94 (1H, m), 3.92 (1H, m), 3.56 (2H, m), 3.37 (3H, m), 2.70 (2H, m), 2.45 (3H, m), 1.22 (3H, m) ppm; MS (ESI) m/z 503.3 (M+H)⁺.

EXAMPLE 996 N² -o-toluenesulfonyl-N³ -[5-(4-amidinophenyl)isoxazolin-3(R,S)-ylformyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Standard cycloaddition techniques using ethylchlorooximido acetate(Aldrich) and 4-cyanostyrene agfforded the desired precursor ethyl-5-(4-cyanophenyl)-isoxazoline carboxylate. Saponification followed by coupling with methyl N² -o-toluylsulfonyl-(S)-2,3-diaminopropionate via standard techniques afforded the desired cyanoprecursor. Formation of the amidine via standard Pinner reaction conditions afforded the desired compound as colorless crystals after HPLC purification; M.P. 84-86° C.; ¹ HNMR(DMSO d₆) δ: 9.45 (b, 1H), 9.35 (b, 1H), 8.40 (q, 1H), 8.21 (dd, 1H), 7.81 (t,2H), 7.77 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.38-7.49 (t, 1H), 7.25 (m, 2H), 5.83 (m, 1H), 3.89 (q, 1H), 3.23-3.71 (m, 3H), 2.98(q, 1H), 2.57 (s,3H) ppm; ESI mass spectrum 474 (M=H, 100 free base); HRMS calcd for C₂₁ H₂₄ N₅ O₆ S 474.144731, found 474.143847.

EXAMPLE 1540 2-(n-Butyloxycarbonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic Acid Bis Trifluorqacetic Acid Salt

Part A: 3-(4-Cyanophenyl)-8-benzyloxycarbonyl-1-oxyo-2,8-diazaspiro[4,5]dec-2-ene.

The title material was prepared from 4-cyanobenzaldoxime (7.0 g, 48 mmol) and 1-benzyloxycarbonyl-4-methylenepiperidine (De Amici, M.; Fr.o slashed.lund, B.; Hjeds, H. Krogsgaard-Larsen, P. Eur. J. Med. Chem. 1991, 26, 625) (11.0 g, 48 mmol) as described in Example 4, Part B. The crude adduct was purified by flash chromatography using a gradient hexane/ethyl acetate solvent system, starting with hexane and progressing to 65% ethyl acetate/hexane in 5% increments to give 14.4 g (86%) of a pale yellow gum. ¹ H NMR (DMSO-d₆, 300 MHz) δ 7.75 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 7.37-7.29 (m, 5H), 5.15 (s, 2H), 3.95-3.83 (m, 2H), 3.51-3.44 (m, 2H), 3.09 (s, 2H), 2.00-1.89 (m, 2H), 1.83-1.70 (m, 2H). IR (KBr) 2228, 1698 cm⁻¹. HRMS (DEP, NH₃) Calc. for (M+H)⁺ : 376.1661. Found: 376.1646.

Part B: 3-(4-Amidinophenyl)-1-oxo-2,8-diazastiro[4.5]dec-2-ene dihydrochloric acid salt.

The intermediate of Part A (4.18 g, 11.1 nmol) was subjected to standard Pinner conditions to give a crude amidine-amine salt, which was purified by flash chromatography using a graduated solvent system starting with chloroform and progressing to 30% methanol in chloroform to give 1.8 g (48%) of the title compound. ¹ H NMR (DMSO-d₆, 300 MHz) δ 9.56 (br s, 1.5H), 9.36 (br s, 1.5H), 7.95 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 4.15-4.14 (m, 1H), 3.43 (s, 2H), 3.36 (s, 4H), 2.05-2.04 (m, 4H). HRMS (DEP, NH₃) Calc. for (M+H)⁺ : 259.1559. Found: 259.1562.

Part C: Methyl 2-(R,S)-(benyloxycarbonylamino)-3-[3(4-amidinothenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]-propionate dihydroiodic acid salt.

The intermediate of Part B (1.67 g, 5.0 mmol) was dissolved in dimethylformamide (20 mL) and sodium bicarbonate (1.27 g, 15.1 mmol) was added. A solution of N-benzyloxycarbonyl-3-iodo-L-alanine methyl ester (Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471) (2.0 g, 5.5 mmol) in dimethylformamide (6 mL) was added and the mixture was stirred at room temperature for 7 d. The solvent was evaporated and the residue was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 1.78 g of impure material. It was chromatographed a second time as above to give 1.72 g (45%) of pure material. ¹ H NMR (DMSO-d₆, 300 MHz) δ 9.16 (br s, 4H), 7.87 (s, 4H), 7.71 (d, J=7.7 Hz, 1H), 7.39-7.30 (m, 5H), 5.10-5.05 (m, 2H), 4.29-4.27 (m, 1H), 3.65 (s, 3H), 3.23 (s, 2H), 2.66-2.60 (m, 4H), 2.46 (m, 2H), 1.75 (m, 4H). IR (KBr) 3300-2950 (br), 1718, 1674 cm⁻¹. HRMS (FAB, glycerol) Calc for (M+H)⁺ : 494.2403. Found: 494.2401.

Part D: Methyl 2-(R,S)-amino-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionate trihydrobromic acid salt.

The intermediate of Part C (1.2 g, 1.6 mol) was dissolved in 30% hydrogen bromide in acetic acid (10 mL) and the solution was stirred at room temperature for 17.5 h. The mixture was diluted with ether and filtered. The solid was washed with ether and dried to give 0.872 g (89%) of a gray solid. ¹ H NMR (DMSO-d₆ +TFA-d, 300 MHz) δ 9.43 (s, 2H), 9.14 (s, 2H), 7.94-7.85 (m, 4H), 4.84 (m, 1H), 3.84 (s, 4H), 3.55-3.42 (m, 6H), 2.16 (br m, 4H). MS (ESI) 360 (M+H).

Part E: Methyl 2-(n-butyloxycarbonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4.5]dec-2-en-8-yl]propionate hydrobromic acid salt.

n-Butylchloroformate (45 μL, 0.35 nmol) was added to a solution of the intermediate of Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was flash chromatographed using a gradient solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 0.249 g of the title compound. MS (ESI) 460 (M+H).

Part F: 2-(n-Butyloxycarbonylamino)-3-[3- (4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic acid bis trifluoroacetic acid salt.

The intermediate of Part E (229 mg, 0.33 mmol) was dissolved in methanol (7 mL) and water (7 mL) and lithium hydroxide hydrate (33 mg, 0.79 mmol). The mixture was stirred at room temperature for 24 h and additional lithium hydroxide hydrate (18 mg, 0.43 mmol) was added. The mixture was stirred for 24 h and the methanol was evaporated. The aqueous residue was diluted with trifluoroacetic acid (0.15 mL) and the mixture was purified by Prep HPLC as described in Example 514A, Part B to give 31 mg (11%) of the title compound. ¹ H NMR (DMSO-d₆, 300 MHz) δ 9.40 (br s, 2H), 9.12 (br s, 2H), 7.91-7.86 (m, 4H), 7.61 (br, 1H), 6.56 (br, 1H), 4.44 (br, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.38 (m, 6H, under water peak), 2.03 (br, 4H), 1.58-1.54 (m, 2H), 1.36-1.34 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). HRMS (FAB, glycerol) Calc. for (M+H)⁺ : 446.2403. Found: 446.2394.

EXAMPLE 1541 2-(R,S)-(3-methylphenylsulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic Acid Bis Trifluoroacetic Acid Salt

Part A: Methyl 2-(R,S)-(m-toluenesulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionate hydrobromic acid salt.

m-Toluenesulfonyl chloride (63 mg, 0.33 mmol) was added to a mixture of the intermediate in Example SP1, Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 19 h. Additional m-toluenesulfonyl chloride (14 mg, 0.07 mmol) was added and the mixture was stirred for 24 h. The solution was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 30% methanol/chloroform to give 0.309 g of a tan solid. HRMS (FAB, glycerol) Calc. for (M+H)⁺ : 514.2124. Found: 514.2137.

Part B: 2- (R,S)-(m-Toluenesulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic acid bis trifluoroacetic acid salt.

The intermediate of Part A (0.277 g, 0.46 mmol) was suspended in 6M hydrochloric acid and the mixture was stirred at room temperature for 2 d. The mixture was concentrated and the residue was purified by Prep HPLC as described in Example 514A, Part B to give 16 mg of the title compound. HRMS (FAB, glycerol) Calc. for (M+H)⁺ : 500.1968. Found: 500.1956.

EXAMPLE 1552 (R,S)-(2-Piperidin-4-yl)ethyl-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione

This material was prepared using the procedures outlined in Example 189, giving the title compoind; mp: 133.4-135.1° C.; ¹ H NMR (400 MHz, CD₃ OD, 55° C.) δ 3.59 (t, J=6.8 Hz, 2H), 3.50 (d, J=17.7 Hz, 1H), 3.38 (bd, J=12.9 Hz, 2H), 3.18 (d, J=17.7 Hz, 1H), 2.98 (m, 4H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d₅), 2.45 (m, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.00 (m, 2H), 1.98 (pentuplet, J=7.1 Hz., 2H), 1.40 (m, 2H).

EXAMPLE 1585A N² -n-butyloxycarbonyl-N³ -[3- (4-piperidinylmethyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ 8.5 (1H, brd), 8.2 (1H, brd), 8.0 (1H, m), 7.4 (1H, d), 4.7 (1H, m), 3.9 (3H, m), 3.6 (1H, m), 3.25 (2H, m), 3.1 (3H, m), 2.9 (2H, m), 2.7 (1H, m), 2.4 (2H, m), 2.2 (3H; m), 1.8 (2H, m), 1.7 (1H, m), 1.5 (2H, m), 1.3 (4H, m), 0.9 (3H, t) ppm; ESI mass spectrum 427.1 (M+H)⁺ free base.

EXAMPLE 1603 Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-piperidinylpropyl)-isoxazolin-5(R,S)-yl-acetyl]-(S)-2,3-diaminopropionate TFA Salt

¹ HNMR (CDCl₃) δ 6.29 (1H, brd), 4.9 (1H, m), 4.45 (1H, m), 4.05 (2H, m), 3.78 (3H, s), 3.68 (1H, m), 3.5 (3H, m), 3.1 (1H, m), 2.96 (2H, m), 2.78 (1H, m), 2.55 (2H, m), 2.36 (2H, m), 1.95 (2H, m), 1.6 (6H, m), 1.5 (2H, m), 1.35 (5H, m), 0.94 (3H, m) ppm; ESI mass spectrum 455 (M+H)⁺ free base.

EXAMPLE 1609 Methyl N² -p-toluenesulfonyl-N³ -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionate TFA Salt

¹ HNMR (CDCl₃) δ 7.7 (2H, d), 7.3 (2H, d), 7.18 (1H, m), 6.4 (1H, m), 4.92 (1H, m), 4.0 (2H,m), 3.7 (1H, m), 3.58 (3H, d), 3.35 (2H, m), 3.1 (1H, m), 2.9 (2H, m), 2.75 (1H, m), 2.55 (1H, m), 2.4 (6H, m), 1.9 (2H, m), 1.6 (5H, m), 1.35 (2H, m) ppm; ESI mass spectrum 509.3 (M+H)⁺ free base

EXAMPLE 1619 N² -(2-methylphenylsulfonyl)-N³ -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl)-(S)-2,3-diaminopropionic Acid IFA Salt

¹ HNMR (DMSO) δ: 8.5(1H, m), 8.18 (1H, m), 8.05 (1H, m), 7.79 (1H, d J=8.057 Hz), 7.51 (1H, t, J=6.958 & 7.324 Hz), 7.37 (2H, m), 4.65 (1H, m), 3.83(1H, m), 3.4 (1H, m), 3.27 (3H, m), 3.07 (1H, m), 2.84 (2H, m), 2.68 (1H, m), 2.59 (3H, s), 2.4 (1H, m), 2.32 (3H, m), 2.08 (1H, m), 1.83 (2H, m), 1.45 (3H, m), 1.26 (2H, m) ppm; ESI mass spectrum 481.4 (M+H, 100)⁺ free base.

EXAMPLE 1621 N² -p-toluenesulfonyl-N³ -[3-(4-pieridinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ 7.73 (2H, d), 7.35 (2H, d), 4.85 (2H, m), 4.05 (1H, m), 3.63 (1H, m), 3.2 (2H, m), 3.0 (4H, m), 2.6 (1H, m), 2.4 (3H, s), 2.42 (2H, m), 2.0 (2H, m), 1.7 (1H, d), 1.6 (3H, m), 1.4 (3H, m) ppm; ESI mass spectrum 481 (M+H, 100)⁺ free base

EXAMPLE 1622 N² -(2-bromophenylsulfonyl)-N³ -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ: 8.5 (1H, brd), 8.2 (1H, m), 8.1 (1H, m), 7.95 (1H, m), 7.8 (1H, m), 7.5 (2H, m), 4.7 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.25 (2H, m), 3.2 (1H, m), 3.0 (1H, m), 2.8 (2H, m), 2.7 (1H, m), 2.4 (2H, m), 2.3 (2H, m), 2.2 (1H, m), 1.8 (2H, m), 1.5 (2H, m), 1.2 (2H, m) ppm; ESI mass spectrum 545.2 (M+H, 100)⁺ free base.

EXAMPLE 1623 N² -(3,5-dimethylisoxazoylsulfonyl)-N³ -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ: 8.5 (1H, d), 8.08 (1H, m), 4.65 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.25 (3H, m), 3.15 (2H, m), 2.85 (2H, m), 2.7 (1H, m), 2.52 (3H, s), 2.4 (1H, m), 2.3 (3H, m), 2.2 (3H, m), 1.8 (2H, brd, d), 1.45 (3H, m), 1.25 (2H, m) ppm; ESI mass spectrum 486.3 (M+H, 100)⁺ free base.

EXAMPLE 1624 N² -(3,4-dimethylthiazoylsulfonyl)-N³ -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ: 8.6 (1H, d), 8.45 (1H, brd), 8.1 (1H, m), 4.65 (1H, m), 3.9 (1H, m), 3.5 (4H, m), 3.05 (2H, m), 2.9 (3H, m), 2.6 (3H, s), 2.45 (3H, s), 2.4 (5H, m), 1.8 (2H, brd. d), 1.5 (2H, m), 1.2 (2H, m) ppm; ESI mass spectrum 502.4 (M+H, 100)⁺ free base.

EXAMPLE 1625 N² -n-butylsulfonyl-N³ -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ 8.5 (1H, m), 8.2 (2H, m), 7.55 (1H, m), 4.7 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.2 (3H, brd, d), 3.1 (1H, m), 2.98 (2H, m), 2.9 (4H, m), 2.4 (1H, d), 2.3 (3H, m), 1.8 (2H, brd, d), 1.7 (2H, m), 1.5 (6H, m), 0.9 (3H, t) ppm; ESI mass spectrum 447.3 (M+H, 100)⁺ free base

EXAMPLE 1627 N² -n-butyloxycarbonyl-N³ -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ 8.5 (1H, m), 8.2 (2H, brd),7.3 (1H, m), 4.7 (1H, m), 4.05 (1H, m), 3.9 (2H, t), 3.5 (1H, m), 3.2 (3H, brd, d), 3.0 (1H, m), 2.8 (2H, m), 2.7 (1H, m), 2.4 (1H, d), 2.25 (3H, m), 1.8 (2H, d), 1.6 (6H, m), 1.4 (7H, m), 0.9 (3H, t) ppm; ESI mass spectrum 441.3 (M+H, 100)⁺ free base.

EXAMPLE 1631 N² -p-toluenesulfonyl-N³ -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (CD₃ OD) δ: 7.7 (2H, m), 7.35 (2H, m), 4.85 (1H, m), 4.05 (2H, m), 3.72 (1H, m), 3.66 (2H, m), 3.56 (1H, m), 3.35 (2H, m), 3.25 (1H, m), 3.14 (1H, m), 2.94 (2H, m), 2.84 (1H, m), 2.55 (1H, m), 2.4 (3H, m), 2.35 (3H, m), 1.95 (2H, m), 1.62 (3H, m), 1.32 (4H, m), ppm; ESI mass spectrum 495.3 (M+H)⁺ free base

EXAMPLE 1656 N² -m-toluenesulfonyl-N³ -[3-(4-amidinopiperidinyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic Acid

M.P. 70-74° C.; ¹ H NMR (DMSO-d₆) δ 8.13 (m,2H), 7.58 (m,2H), 7.44-7.38 (m, 5H), 4.74 (m, 1H), 3.88-3.80 (m, 5H), 3.40 (m, 1H), 3.14-2.99 (m, 4H), 2.74 (m,2H), 2.37 (s,3H), 2.17 (dd, J=7.32, 14.28 Hz), 1.88 (d, J=13.18 Hz, 2H), 1.53 (q, J=11.35 Hz, 2H) ppm; High Res Mass Spectrum calculated (M+H)⁺ 495.202580; found (M+H)⁺ 495.200904.

EXAMPLE 1657 N² -p-toluenesulfonyl-N³ -[3-(4-amidinopiperidinyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic

Part A: The isoxazoline acetic acid was prepared starting from 1-t-butylcarbamate-4-piperidine carboxaldehyde (Jacobs, R., et al, EP 532177) through methods previously described. ¹ H NMR (CDCl₃) δ 4.94 (m, 1H), 4.18-4.05 (m, 2H), 3.18 (dd, J=10.25, 17.20 Hz, 1H), 2.90-2.67 (m, 4H), 2.63 (m, 2H), 1.87 (m, 2H), 1.56-1.45 (s, 9H), 1.46 (s, 9H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 330 (100%); IR (KBr) 3100, 1734, 1690, 1648, 1430, 1276, 1168, 758 cm⁻¹.

Part B: The acid from Part A (360 mg, 1.2 mmol) was coupled with methyl L-N² -p-toluylsulfonyl-diaminoproprionate using procedure described in Example 43D. The crude product was chromatographed on silica gel (2% MeOH/CH₂ Cl₂) to afford 270 mg (41%) of a white foam. M.P. 55-60° C.; ¹ H NMR (CDCl₃) δ 7.72 (d, J=8.06 Hz, 2H), 7.30 (d, J=8.06 Hz, 2H), 6.45 (m, 1H), 5.73 (dd, J=8.42, 16.11 Hz, 1H), 4.90 (m, 1H), 4.13 (m, 2H), 4.01 (m, 1H), 3.58 (s, 3H), 3.60-3.49 (m, 2h), 3.10 (m, 1H), 2.84-2.72 (m, 3H), 2.57 (m, 2H), 2.48 (m, 1H), 2.42 (s, 3H), 1.85 (d, 2H), 1.55-1.46 (brd m, 2H), 1.46 (s, 9H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 584 (100%); IR (KBr) brd 3300, 1746, 1688, 1428, 1238, 1164 cm⁻¹.

Part C: To the product from Part B (230 mg, 0.41 mmol) was added 10 ml of 30% TFA/CH₂ Cl₂ and the mixture was stirred for 3h. The solvents were removed in vacuo. To the residue was added 2 ml DMF, triethylamine (0.39 ml, 2.8 mmol), and bis-tertbutyloxycarbonyl-3,5-dimethylpyrazole-1-carboxamidine (165 mg, 0.49 mmol) (Kim, et al, Tet. Lett.,1993, 34, 7677) and the mixture was stirred for 24 h. The reaction was partitioned with EtOAc/water. The organic layer was washed successively with water, brine and dried (MgSO₄). Chromatography on silica gel (2% MeOH/CH₂ Cl₂) afforded 203 mg (71%) of a white foam. M.P. 69-75° C.; ¹ H NMR (CDCl₃) δ 10.18 (brd m, 1H), 7.72 (d, J=8.05 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 6.40 (m, 1H), 5.65 (m, 1H), 4.87 (m, 1H), 4.30 (brd, 1H), 4.05 (brd, 1H), 3.60-3.51 (s+m, 5H), 3.09 (m, 3H), 2.78 (m, 3H), 2.42 (s, 3H), 1.89 (m, 2H), 1.73 (m, 2H), 1.63 brd m, 2H), 1.49 (s, 18H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 709.5 (100%); IR (KBr) 3300-2800, 2210, 1742, 1660, 1600, 1546, 1446, 1332, 1162, 1092 cm⁻¹.

Part D: To the product from Part C (160 mg, 0.23 mmol) was added 6 ml of 1:1 MeOH/water and lithium hydroxide (28 mg, 0.67 mmol). The mixture was stirred for 18 h and the solvents were removed in vacuo. The residue was taken up in water and acidified with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO₄), filtered and concentrated to afford 118 mg (76%) of the acid. To the acid was added 10 ml 30% TFA/CH₂ Cl₂ and the mixture was stirred 24h. The solvents were removed and the TFA salt was purified by HPLC to afford 20 mg product. M.P. 134-140° C.; ¹ HNMR (DMSO-d₆) δ 7.9 (q, 1H), 7.66 (d, j=8.06 Hz, 2H), 7.46 (s, 3H), 7.36 (d, j=8.06 Hz, 2H), 4.72 (m, 1H), 3.80 (d, j=13.18 Hz, 2H) 3.61 (m, 1H), 3.41-3.18 (m, 5H), 3.13-2.99 (m, 3H), 2.75 (m 2H), 2.36 (s,3H), 2.22 (m, 1H), 1.88 (d, j=12.8 Hz, 2H), 1.53 (m, 2H) ppm ; Mass spectrum (ESI) m/z 495.2 (100%), high res Mass Spectrum (M+H)⁺ calculated 495.20258, found 495.202476

EXAMPLE 1673 N² -p-toluenesulfonyl-N³ -[3-(4-amidinopiperidinylmethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

¹ HNMR (DMSO) δ: 8.1 (2H, m), 7.65 (2H, d), 7.35 (2H, d), 4.7 (1H, m), 3.8 (3H, m), 3.4 (2H, m), 3.1 (1H, m), 3.0 (3H, m), 2.7 (1H, m), 2.4 (1H, m), 2.35 (3H, s), 2.25 (1H, m), 2.2 (3H, m), 1.85 (1H, m), 1.7 (2H, m), 1.6 (1H, m), 1.2 (3H, m) ppm; ESI mass spectrum 509.4 (M+H, 100)⁺ free base.

EXAMPLE 1704 N² -n-butyloxycarbonyl-N³ -[3-(quanidinopropyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: The title compound was prepared following the [3+2] cycloaddition methodology employed for example 4 from the readily accessible Boc-aminopropylchlorooxime (obtained from a sequence of steps from commerical (Aldrich) aminopropanol (aldehyde obtained via Moffat et. al. J. C. S. Perk. Trans. 1. 1991, 5, 1041-1051)) and butylvinyl ester. LiOH saponification in methanol:water (9:1), then afforded the desired acetic acid compound in 90% yield. ¹ HNMR (CDCl₃) δ 4.90 (m, 1H), 4.70 (brd, s, 1H), 3.08 (m, 3H), 2.68 (m, 2H), 2.57 (dd, 1H), 2.34 (t,2H), 1.75 (m, 2H), 1.41 (s, 9H) ppm; ESI mass spectrum 287(M+H, 100).

Part B: The product from part A was then coupled to methyl N² -n-butyloxycarbonyl-(S)-2,3-diaminopropionate via the procedure used in example 4, to obtain Methyl N² -n-butyloxycarbonyl-N³ -[3-(Boc-aminopropyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate in 50% yeild. Treatment with trifluoroaceticacid in dichloromethane, evaporation of solvent then afforded the anilino intermediate as the TFA salt. Standard guanidine formation techniques then afforded the di-Bocguanidinopropyl analog in 90% yield. Removal of the Boc-protecting groups with TFA afforded example 601 as the TFA salt. Alternatively, saponification of the methyl ester followed by removal of the Boc-protecting groups with TFA also afforded the desired product as the TFA salt in 80% overall yield. ¹ H NMR (CD₃ OD) δ: 4.93 (m, 1H), 4.29 (brd.m, 1H), 4.02 (t, 2H), 3.65 (m, 1H), 3.32 (m, 1H), 3.21 (m, 2H), 3.09 (dd, J=10.2 & 17.6 Hz, 1H), 2.79 (dd, J=7.32 & 17.1 Hz, 1H), 2.52 (dd, J=2.2 & 8.8 Hz, 1H), 1.84 (m, 2H), 2.39 (m, 3H), 1.58 (m, 2H), 1.36 (m, 2H), 0.9 (t, 3H,) ppm; HR MS calcd. for ESI mass spectrum 529 (M+H, 100) for free base.

EXAMPLE 1756 N² -p-toluylsulfonyl-N³ -[3-(4-piperidinylmethylaminocarbonyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic Acid

Part A: To a mixture of tert-butyl vinylacetic acid (11.2 g, 0.079 mol) and ethylchlorooximidoacetate (11.37 g, 0.075 mol, Aldrich) in a mixture of 2:1 THF/water at 0° C. was added sodium bicarbonate (19.9 g, 0.237 mol). The reaction was stirred for 3d at room temperature, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried with MgSO₄. The crude oil was chromatographed on silica gel (7:1 hexanes/ EtOAc) to afford 7.46 g (39%) of product as a colorless oil; ¹ H NMR (CDCl₃) δ 5.15 (m, 1H), 4.39 (q, J=7.32 Hz, 2H),3.43 (dd, J=10.99, 17.58 Hz, 1H), 3.03 (dd, J=7.69, 17.58 Hz, 1H), 2.81 (dd, J=5.86, 16.11 Hz, 1H), 2.59 (dd, J=7.69, 16.11 Hz, 1H),1.46 (s, 9H), 1.39 (t, J=7.32 Hz, 3H); Mass Spectrum (NH₃ -CI) m/z (M+H)⁺ 258 (12%), (M+NH₄)⁺ 275 (100%).

Part B: The ethyl ester (3 g, 0.012 mol) from Part 1A was selectively hydrolyzed with LiOH (0.64 g, 0.015 mol) in 1.5:1 methanol/water at 0° C. for 1.5 h. The methanol was removed in vacuo. The aqueous residue was acidified with 10% citric acid and extracted with EtOAc and dried with MgSO₄. The crude solid was recrystallized with CH₂ Cl₂ /hexanes to afford 2 g (75%) white crystals. mp 83-86° C.; ¹ H NMR (CDCl₃) δ 5.23 (m, 1H), 3.44 (dd, J=10.98, 17.58 Hz, 1H), 3.05 (dd, J=8.05, 17.95 Hz, 1H), 2.82 (dd, J=5.85, 16.11 Hz, 1H), 2.64 (dd, J=7.32, 16.11 Hz, 1H), 1.46 (s, 9H) ppm; Mass spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 247 (90%).

Part C: 4-Aminomethyl piperidine (3.8 g, 0.034 mol, Aldrich) was selectively protected in 68% yield with carbobenzoxyimidazole using the method of Sharma, et al. (J. Med. Chem. 1989, 32, 357). To the crude 4-Cbz-aminomethyl piperidine (3 g, 0.012 mol) in 30 ml dioxane at 0° C. was added 13 ml of 1N sodium hydroxide and di-t-butyl dicarbonate (2.7 g, 0.013 mol). The reaction was stirred at room temperature for 48 h. The dioxane was removed in vacuo and the residue was suspended in EtOAc and washed successively with 10% citric acid, sat'd NaHCO₃, brine and dried (MgSO₄). Recrystallization with CH₂ Cl₂ /hexane afforded 1 g of white crystals (24%) mp 91-96°C.; ¹ H NMR (CDCl₃) δ 7.32 (s, 5H), 5.10 (s, 2H), 4.60 (t, 1H), 4.20 (brd, 2H), 3.0 (brd, 2H), 2.75 (brd, 2H), 1.65 (d, 2H), 1.45 (s, 9H), 1.12 (brd, 2H) ppm; Mass spectrum (NH₃ -CI) m/z (M+H)+349 (31%), (M+H-56)+293 (100%); IR (KBr) 1698, 1530 cm⁻¹ ; Analysis for C19H28N2O4 calc'd C:65.49, H:8.10, N:8.04; found C:65.78, H:7.82, N:8.06.

Part D: To the compound from part C (94 mg, 2.7 mmol) was added 50 ml EtOH and 100 mg of 10% Pd/C and the mixture was hydrogenated at 40 PSI for 18 h. Filtration and removal of the solvent afforded 569 mg (98%) solid. mp 84-88° C.; ¹ H NMR (CDCl₃) δ 4.70 (brd, 1H), 3.10 (d, 2H), 3.0 (t, 2H), 2.95 (brd, 2H), 2.64 (t, 2H), 1.70 (d, 2H), 1.46 (s, 9H), 1.20 (m, 2H) ppm; Mass spectrum (NH₃ -CI) m/z (M+H)⁺ 215 (100%); IR (KBr) 2972-2800, 1694 cm⁻¹.

Part E: To the acid from Part B (360 mg, 1.6 mmol) in 5 ml EtOAc was added triethylamine (0.67 ml, 4.80 mmol) followed by TBTU (560 mg, 1.73 mmol). After 15 minutes the amine from Part D (370 mg, 1.7 mmol) was added and the reaction was stirred for 24 h. The reaction mixture was washed successively with 10% citric acid, water, sat'd NaHCO₃, brine and dried (MgSO₄). The residue was chromatogrphed on silica gel (3:2 Hexanes/EtOAc) to afford 0.41 g (61%) white foam. ¹ H NMR (CDCl₃) δ 5.04 (m, 1H), 4.63 (d, J=13.18 Hz, 2H), 4.53 (d, J=13.18 Hz, 1H), 3.52-3.38 (m, 1H), 3.15-2.99 (m, 4H), 2.77 (m, 2H), 2.59-2.49 (m, 5H),1.78 (t, J=10.0 Hz 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.25 (m, 2H); Mass Spectrum (NH3-CI) m/z (M+H)+426.3 (29%), (M+H-56)+370.2 (43%); IR (KBr) 2976, 2930, 1714, 1632, 1592, 1522, 1476, 1452, 1392, 1366, 1168 cm⁻¹.

Part F: To the product of Part E (380 mg, 0.89 mmol) was added 10 ml of 30% TFA/CH₂ Cl₂ and stirred for 4 h. The solvents were removed and 10 ml dioxane was added. The mixture was cooled to 0° C. and 2 ml of 1N NaOH was added followed by di-t-butyldicarbonate (0.22 g, 0.98 mmol). The reaction was stirred for 48 h at room temperature. The reaction was concentrated and partitioned with EtOAc and water. The aqueous layer was acidified with 10% citric acid, extracted with EtOAc and dried (MgSO₄). The crude residue was chromatographed on silica gel (10% MeOH/CH₂ Cl₂) to afford 0.23 g (69%) of a white foam. mp 159-165° C. ¹ H NMR (DMSO-d₆) δ 6.95 (t, J=5.86 Hz, 1H), 4.87 (m, 1H), 4.33 (d, J=13.18 Hz, 1H), 4.09 (d, J=13.90 Hz, 1H), 3.31 (m, 1H), 3.07 (t, J=12.82 Hz, 1H), 2.99 (dd, J=3.66, 8.05 Hz, 1H), 2.93 (dd, J=3.66, 7.70 Hz, 1H), 2.82 (t, J=5.86 Hz, 2H), 2.69 (t, 12.82 Hz, 1H), 2.39 (m, 1H), 2.27 (dd, J=7.69, 14.6 Hz, 1H), 1.67-1.60 (m, 3H), 1.37 (s, 9H), 1.04 (t, J=13.5 Hz, 1H) ppm; Mass Spectrum (NH3-CI) m/z (M+NH₄)⁺ 387 (100%); IR (KBr) 3352, 1692, 1630, 1588, 1518, 1448, 1210, 1176, 1140 cm⁻¹.

Part G: The product of Part F (217 mg, 0.59 imol) was coupled with methyl L-N² -p-toluylsulfonyl-diaminoproprionate according to procedure in Example 43D. The crude material was chromatographed on silica gel (2% MeOH/CH₂ Cl₂) to afford 230 mg (63%) foam. ¹ H NMR (CDCl₃) δ 7.72 (d, 2H), 7.30 (d, 2H), 6.40-6.32 (m, 1H), 5.1 (m, 1H), 4.70 (brd, 2H), 4.50 (d, 1H), 3.99 (brd, 1H), 3.65 (s, 3H), 3.50 (m, 2H), 3.15-2.99 (m, 3H), 2.85-2.55 (m 2H), 2.45 (s, 3H), 1.85 (brd, 4H), 1.46 (s, 9H), 1.29 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 624.5 (72%), (M+H-56)⁺ 568.3 (98%).

Part H: The product of Part G (200 mg, 0.32 nmol) was hydrolyzed with lithium hydroxide (20 mg, 0.48 mmol) in 1:1 MeOH/water for 48 h. The solvents were removed in vacuo and the residue dissolved in water, acidified with 10% citric acid, extracted with EtOAc and dried (MgSO₄). The crude acid was treated with 15 ml of 30% TFA/CH₂ Cl₂ for 24 h. The crude TFA salt was purified via HPLC to give 21 mg (11%) foamy solid. ¹ HNMR (DMSO-d₆) δ8.15 (m,1H), 7.73 (m,1H), 7.63 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.05 Hz, 2H), 4.90 (m,1H), 4.37 (d,j=13.5 Hz, 2H), 4.14 (d,j=2H, j=10.9 Hz), 3.83 (q,j=9 Hz,1H), 3.35 (m,2H), 3.12-2.90 (m,3H), 2.74 (m, 2H), 2.33 (s,3H), 2.50-2.20 (m, 3H), 1.90-1.70 (m,4H), 1.35 (m,2H) ppm; High Res Mass Spectrum (M+H)⁺ calculated 510.202246, found 510.203464.

EXAMPLE 1769 N² -p-toluenesulfonyl-N³ -[3-(N-(4-piperidinylmethyl)-N-(methyl)aminocarbonyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopronrionic Acid Trifluoroacetic Acid Salt

Part A: To 4-tertButyloxycarbonyl-piperidinyl-methyl amine described previously (1.93 g, 0.009 mol) in 20 ml CH₂ Cl₂ at 0° C. was added pyridine (1.1 ml, 0.014 mol) followed by slow addition of trifluoroacetic anhydride (1.4 ml, 0.009 mol). The reaction was stirred at 0° C. for 1 h, then it was diluted with CH₂ Cl₂ washed successively with 10% citric acid, water, sat'd NaHCO₃, brine and dried (MgSO₄). Recrystallization from CH₂ Cl₂ /Hexanes afforded 2.4 g (86%) of a bright yellow solid. mp 123-125° C.; ¹ H NMR (CDCl₃) δ 4.74 (m, 1H), 4.56 (d, J=13 Hz, 1H), 4.0 (d, J=12 Hz, 1H), 3.14 (m, 3H), 2.75 (t, J=13 Hz, 1H), 1.82 (d, 3H), 1.45 (s, 9H) 1.28 (m, 2H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 328 (100%), (M+NH₄ -56)+272.1 (100%); IR (KBr) 3354, 1686, 1526, 1200, 1140 cm⁻¹.

Part B: To the product of Part A (400 mg, 1.29 mmol) in 2 ml DMF was added NaH (62 mg, 1.6 mmol) After 1 h, methyl iodide (0.1 ml, 1.6 mmol) was added and the reaction was immersed in a 60° C. oil bath for 24 h. The reaction was cooled and partioned between EtOAc and water. The organic layer was washed with water, brine and dried (MgSO₄). The reaction had not gone to completion and was resubjected to the above conditions and after work up afforded 322 mg (77%) yellow oil. The crude trifluoroacetate was placed in 20 ml of 1:1 MeOH/water and K₂ CO₃ (150 mg, 1.1 mmol) was added and the reaction was stirred for 36 h. The solvents were removed in vacuo and the residue partioned with EtOAc/water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried (MgSO₄), filtered and concentrated to yield 194 mg (89%) oil. ¹ H NMR (CDCl₃) δ 3.15 (m, 4H), 2.85 (s, 3H), 2.80 (brd s, 1H), 2.61 (t, J=12Hz, 2H), 1.63 (d, J=10.6 Hz, 2H), 1.45 (s, 9H), 1.25 (m, 2H), 0.87 (m, 1H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+H)⁺ 229 (100%), (M+NH₄)⁺ 246 (15%); IR (KBr) 2924,1696,1160 cm⁻¹.

Part C: The product of Part B (173 mg, 0.76 mmol) was coupled with the acid (from Part B previous example) according to procedure in Example 43D to yield 177 mg (54%) yellow oil. ¹ H NMR (CDCl₃) δ 5.02 (m, 1H), 4.59-4.50 (brd m, 2H), 3.48 (dd, J=10.62,17.58 Hz, 1H), 3.15-3.02 (m, 4H), 2.86 (s, 3H), 2.77 (m, 2H), 2.59 (m, 1H), 2.0-1.91 (brd m, 1H), 1.73 (t, J=11.72 Hz, 2H), 1.46 (s, 18H), 1.28 (m, 2H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+H)⁺ 440.2 (100%), (M+NH₄)⁺ 457.3 (23%), (M+H-56)⁺ 384.2 (73%); IR (KBr) 2976, 2932, 1730, 1694, 1634, 1162 cm⁻¹

Part D: The product of Part C (170 mg, 0.387 mmol) was deprotected and selectively reprotected as in Part 1F to afford a yellow foam. ¹ H NMR (CDCl₃) δ 5.10 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 3.50 (m, 1H), 3.12 (m, 4H), 2.80 (s, 3H), 2.78 (m, 1H), 2.70 (m, 2H), 1.90 (brd m, 1H), 1.75 (brd m, 2 H), 1.45 (s, 9H), 1.25 (brd m, 2H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 401 (100%).

Part E: The product of Part D (148 mg, 0.386 mmol) was coupled with methyl L-N² -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude material was chromatographed on silica gel (3% MeOH/CH₂ Cl₂) to afford 230 mg clear glass containing minor impurities. ¹ H NMR (CDCl₃) δ 7.72 (d,2H), 7.33 (d,2H), 6.35 (m, 1H), 5.10 (m,1H), 4.61 (brd m, 1H), 4.45 (brd m, 1H), 3.97 (brd m, 1H), 3.63-3.54 (s+m, 5H), 3.48-3.30 (m, 2H), 3.15 (brd m,4H), 2.85 (s, 3H), 2.75-2.5 (m, 4H), 2.45 (s, 3H), 1.78 (brd m, 2H), 1.46 (s,9H), 1.30 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 638.5 (100%)

Part F: The product of Part E (230 mg, 0.36 mmol) was subjected to hydrolysis and deprotection and purification by HPLC to afford 134 mg (58%) of a white powder. mp 69-72° C.; ¹ HNMR (DMSO-d₆) δ 8.35 (brd m, 2H), 8.10 (brd m, 2H), 7.65 (d, J=6.96 Hz, 2H), 7.35 (d, j=8.05 Hz, 2H), 4.83 (m,1H), 4.36 (d,j=13.6 Hz, 1H), 4.12 (d,j=10 Hz, 1H), 4.0-3.5 (m,6H), 3.35 (m,1H), 3.14 (t,j=10.98 Hz, 1H),2.83 (m,1H), 2.59 (s, 3H), 2.55 (m,1H), 2.36 (s, 3H), 2.35 (m,1H), 2.0 (brd m,1H), 1.80-1.74 (brd m, 2H), 1.18 (m, 2H) ppm; Mass Specturm (ESI) m/z (m+H)⁺ 524.4 (100%); IR (KBr) 3300-2800 brd, 1736,1632, 1202,1162 cm⁻¹.

EXAMPLE 1774 N² -p-toluylsulfonyl-N³ -[3-(4-piperidinylaminocarbonyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionate

Part A: The acid (from Part B described previously, 225 mg, 0.98 mmol) was coupled with 1-tertbutyloxycarbonyl-4-aminopiperidine (Obase, H; et al, J.Het. Chem. 1983, 20, 565) as described in Example 43D.A white foam was obtained in 78% yield. ¹ H NMR (CDCl₃) δ 6.50 (d, J=8.05 Hz, 1H), 5.13 (m, 1H), 3.43 (dd, J=10.62, 17.95 Hz, 1H), 3.04 (dd, J=7.69, 18.3 Hz, 1H), 2.87 (t, J=12.45 Hz, 2H), 2.76 (dd, J=6.22, 16.11 Hz, 1H), 2.57 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=9.88 Hz, 2H), 1.46 (s,18H), 1.41 (m, 2H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+H)⁺ 412.2 (69%), (M+NH₄)⁺ 429.3 (50%), (M+NH₄ -56)⁺ 373.2 (100%); IR (KBr) 3424,2866,1728,1692,1536,1426,1368,1238,1162 cm⁻¹.

Part B: The product of Part A (300 mg, 0.73 mmol) was deprotected with TFA and selectively reprotected with di-t-butyldicarbonate to afford 270 mg of a white foam. ¹ H NMR (CDCl₃) δ 6.64 (d, J=8.05 Hz, 1H), 5.2 (m, 1H), 4.10-3.95 (m, 3H), 3.47 (dd, J=10.99, 17.96 Hz, 1H), 3.08 (dd, J=7.69, 17.95 Hz, 1H), 2.89 (t+dd, 3H), 2.72 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=12.82 Hz, 2H), 1.46 (s, 9H), 1.46 (brd m, 2H) ppm; Mass Spectrum (NH₃ -CI) m/z (M+NH₄)⁺ 373 (100%).

Part C: The product of Part B (260 mg, 0.73 mmol) was coupled with methyl L-N² -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude foam was chromatographed on silica gel (2% MeOH/CH₂ Cl₂) to afford 289 mg (65%) of a white foam. ¹ H NMR (CDCl₃) δ 7.71 (d, J=8.06 Hz, 2H), 7.31 (d, J=8.42 Hz, 2H), 6.65 (dd, J=6.59 Hz, 1H), 6.36 (t, J=5.86 Hz, 1H), 5.15 (m, 1H), 4.10-3.96 (m, 4H), 3.63-3.56 (s+m, 5H), 3.45-3.35 (m, 1H), 3.09 (m,1H), 2.85 (t, J=12.45 Hz, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 1.94 (d, J=12.82 Hz, 2H), 1.45 (s+m, 9+2H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 610.3 (100%).

Part D: The product of Part C (289 mg, 0.47 mmol) was subjected to hydrolysis and deprotection and purification as previously described to afford 224 mg (78%) white powder. mp 88-91° C.; ¹ HNMR (DMSO-d₆) δ 8.66-8.57 (d+m, j=7.69Hz, 2H), 8.30 (brd m, 1H), 8.07 (m, 2H), 7.64 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.06 Hz, 2H), 4.94 (m,1H), 3.96 (m, 1H), 3.87 (q,j=6.95 Hz, 1H), 3.30-3.24 (m,4H), 3.08-2.89 (m,4H), 2.46 (m,1H), 2.37 (s,3H), 2.37 (m,1H), 1.87 (d,j=10.9 Hz,2H), 1.73 (q,j=10.6 Hz,2H) ppm; Mass Spectrum (ESI) m/z (M+H)⁺ 496.3 (100%); IR (KBr) 3300-2800 brd, 1736,1666, 1544 1162 cm⁻¹

EXAMPLE 1945 N² -3-Methylphenylsulfonyl-N³ -[3-[2-(piperidin-4-yl)ethyl]isoxazolin-5(R,S)-ylacetyl)-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: Methyl (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetate

To a solution of Methyl Vinylacetate 352 g, 0.35 mol) in CH₂ Cl₂ (175 mL) was added a 5% solution of sodium hypochlorite (210 mL, 0.15 mol). The mixture was stirred rapidly at room temperature and a solution of (3-N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (Example 189, Part B, 17.60 g, 68.6 mmol) in CH₂ Cl₂ (50 mL) was added over 15 h. The mixture was diluted with water and CH₂ Cl₂, the layers separated, and the aqueous washed with CH₂ Cl₂. The combined organic was dried (MgSO₄), concentrated in vacuo, and the oily residue purified using flash chromatography (10-50% EtOAc/hexanes step gradient), giving 10.35 g (42%) of the desired isoxazoline as a golden oil; Anal. Calcd for C₁₈ H₃₀ N₂ O₅ : C, 61.00; H, 8.53; N, 7.90. Found: C, 61.07; H, 8.50; N, 7.80.

Part B: (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic Acid

To a solution of methyl (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)ylacetate (10.35 g, 29.20 mmol) in THF (100 mL) was added 0.5 M LiOH (80 mL, 40 mmol). The resulting solution was stirred at room temperature overnight (18 h) and then concentrated in vacuo to one-half volume. The pH was adjusted to 4, and the resulting cloudy solution washed with CH₂ Cl₂ (4×30 mL). The combined organic was dried (MgSO₄), concentrated in vacuo, and placed under vacuum until constant weight was achieved, affording 9.74 g (98%) of the desired acid; Anal. Calcd for C₁₇ H₂₈ N₂ O₅ : C, 59.98; H, 8.29; N, 8.23. Found: C, 60.19; H, 8.42; N, 7.87.

Part C: t-Butyl N² -3-Methylphenylsulfonyl-N³ -[(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate

To a solution of (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic acid (165 mg, 0.485 mmol) and t-butyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate hydrochloride (170 mg, 0.485 mmol) in DMF (5 mL) was added Et₃ N (0.2 mL, 1.4 mmol) followed by TBTU (160 mg, 0.498 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (50 mL). It was washed with water (4×20 mL), sat. NaHCO₃ (30 mL), sat. NaCl and dried (MgSO₄). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 271 mg (88%) of the desired amide; MS (ESI, e/z, relative intensity): 637 (M+H)⁺, 20%, 537 (M+H-C₄ H₉ CO₂)⁺, 51%.

Part D: N² -3-Methylphenylsulfonyl-N³ -[(3-(2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt

To a solution of t-butyl N² -3-methylphenylsulfonyl-N³ -[(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (261 mg, 0.410 mmol) in CH₂ Cl₂ (2 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3×5 mL). The resulting white powder was purified using reverse phase HPLC, giving 202 mg (83%) of the desired piperidine; MS (ESI, e/z, relative intensity): 481 (M+H)⁺, 100%.

EXAMPLE 2103 N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt

Part A: Methyl N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ [3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R S)-ylacetyl]-(S)-2,3-diaminopropionate

Methyl N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ -Boc-(S)-2,3-diaminopropionate (1.40 mmole) was stirred with 4 M HCl/dioxane (10 mL, 40 mmol) at 25° C. After 2.5 h, the volatiles were removed in vacuo, and residual HCl/dioxane was removed by repeated addition of toluene and evaporation. To the residue was added 3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S)-ylacetic acid (510 mg, 1.47 nmol), TBTU (480 mg, 1.50 mmole) and DMF (15 mL). Triethylamine (0.830 mL, 603 mg, 5.97 mmole) was added and the reaction mixture was stirred at 25° C. overnight. The mixture was diluted with water (70 mL) extracted with 3× ethyl acetate. The combined organic extracts were washed with 2× water, 5% pH 4 potassium hydrogen phthalate buffer (25 mL), 5% aqueous sodium bicarbonate (25 mL) and brine. After drying over MgSO4, removal of volatiles and purification by flash chromatography (ethyl acetate) provided 0.598 g of the desired product in 96% purity, as assessed by analytical HPLC (4.6 mm×25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min, product at 12.9 min); ¹ H NMR (300 MHz, CDCl₃) δ 7.84 (m, 2H), 7.63 (m, 2H), 6.52 (bm, 1H), 6.07 (bd, 1H), 5.11 (bm, 1H), 4.02 (bm, 1H), 3.66/3.67 (2s, 3H, diastereomers, methyl ester), 3.67-3.45 (m, 3H), 3.15 (m, 1H), 2.60/2.61 (2s, 3H, diastereomers, isoxazole methyl), 2.76-2.55 (m, 2H), 2.38/2.41 (2s, 3H, diastereomers, isoxazole methyl), 1.56 (s, 9H, t-Bu); MS (ESI): m/e 607.2 (M+H)⁺.

Part B: N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2.3-diaminopropionate

To a solution of 200 mg (0.329 mmole) of methyl N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ [3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diamino-propionate in 15 mL of THF/MeOH/water 1:1:1 was added 138 mg (3.29 mmole) of LiOH. After 2 h, analytical HPLC (see conditions in Part A, product at 11.7 min) indicated the reaction was 97% complete. Removal of volatiles and purification by flash chromatography provided 0.164 g 91% pure (see HPLC conditions in Part A) of the desired product as a mixture of free acid and lithium salt (as indicated by 0.55% Li by elemental analysis); ¹ H NMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=8.0 Hz, 2H), 7.96 (m, 1H), 7.75 (dd, J=1.5, 8.4 Hz, 2H), 5.02 (m, 1H), 3.58-3.08 (m, 5H), 2.55 (s, 3H, isoxazole methyl), 2.60-2.37 (m, 2H), 2.34 (s, 3H, isoxazole methyl), 1.45 (s, 9H, t-Bu); MS (ESI): m/e 593.3 (M+H)⁺, m/e 493.2 (M-Boc)⁺.

Part C: N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt

A solution of 137 mg (0.231 mmole) of N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ [3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diamino-propionate in 4 mL of CH₂ Cl₂ and 2 mL of TFA was stirred for 4 h, then diluted with 60 mL of ether. The precipitate was dried to give 0.103 g of the desired product as a white solid, which was determined to be 96% pure by analytical HPLC (see HPLC conditions in Part A); ¹ H NMR (300 MHz, DMSO-d₆) δ 9.79 (bs, 1H), 9.72 (bs, 1H), 9.29 (bs, 2H), 8.25 (bs, 1H), 8.16 (m, 1H), 7.87 (s, 4H), 5.02 (bm, 1H), 3.78 (bs, 1H), 3.60-3.08 (m, 4H), 2.54 (s, 3H, isoxazole methyl), 2.34 (s, 3H, isoxazole methyl), 2.62-2.34 (m, 2H); MS (ESI): m/e 493.3 (M+H)⁺ ; HRMS (FAB): m/e calculated for C₂₀ H₂₅ N₆ O₇ S (M+H)⁺ 493.150544; found 493.148681.

EXAMPLE 2103a N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt (Alternative Hydrolysis Procedure)

Methyl N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate hydrochloride salt (Part B, replacing ammonium acetate with ammonium chloride, 1.3 g, 2.6 mmol) was stirred in 6N HCl (150 ml) at room temperature for 20 hours. Solvent was evaporated under reduced pressure to give the crude hydrochloride salt as a white solid (1.1 g, 87%). Purification of 0.17 g crude product by preparative HPLC (Vydac C18 reverse phase column; 2×25 cm; 10 ml/min flow rate; 254 nM; gradient: from 100% H₂ O with 0.05% TFA to 20% H₂ O and 80% CH₃ CN with 0.05% TFA in 50 minutes) yielded 0.12 g (70.6%) of the title compound as a white powder. Chiral HPLC analysis (SFC, Chiralcel OD; 0.46×25 cm; 30° C.; 2.0 ml/min flow rate; 0.1% TFA/22% MeOH/78% CO₂ ; 280 nM; 150 atm) showed >99% d.e. with respect to the (S,S)-diastereomer and >98% chemical purity. MS (ESI): m/e 493 (M+H)⁺. HRMS (FAB): m/e calculated for C₂₀ H₂₄ N₆ O₇ S (M+H)⁺ 493.150649; Found 493.150544.

EXAMPLE 2103b N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid Methanesulfonate Salt

Part A: Methyl N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ [3-(4-(cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5(R)-ylacetic acid (252 mg, 0.725 mmol), methyl N² -(3,5-dimethylisoxazole-4-sulfonyl-(S)-2,3-diaminopropionate hydrochloride (28.24 g, 70% purity, 63.0 mmol) in DMF (200 mL) was added TBTU (28.90 g, 90 mmol). The mixture was cooled to 0° C. and Et₃ N (31.4 mL, 225 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature overnight (18 h), then was diluted with EtOAc (500 mL). It was washed with water (4×200 mL), sat. NaHCO₃ (100 mL), sat. NaCl (100 mL) and dried (MgSO₄). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 25.06 g (81%) of the desired amide; ¹ H NMR (300 MHz, CDCl₃) δ 8.77 (bs, 1H), 8.22 (t, J=5.9 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J 7.0 Hz, 1H), 3.55 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H), 3.42 (m, 1H), 3.16 (m, 2H), 2.54 (s, 3H, coincident with m, 1H, DMSO-d₅), 2.37 (dd, J=14.6, 7.0 Hz, 1H), 2.33 (s, 3H).

Part B: Methyl N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Acetate Salt

Into a solution of methyl N² -(3,5-dimethylisoxazole-4-sulfonyl)-N³ [3-(4-(cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (25.06 g, 51.17 mmol) in anhydrous MeOH (750 mL) at 0° C. was bubbled HCl gas for 3 hours. The resulting solution was then allowed to warm to room temperature overnight (18 h), after which the solvent was evaporated in vacuo, to give an oil. The oily residue was triturated with ether (3×100 mL) and the resulting solid placed under vacuum until constant weight was achieved. The crude imidate was then dissolved in MeOH (1 L) and ammonium acetate (20.0 g, 259 mmol) added. The resulting mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was then crystallized from EtOH, giving 21.75 g of crude amidine. A portion of this material (8.5 g) was purified using flash chromatography (20% MeOH-EtOAc) to give 3.77 g (33%) of 97.6% pure amidine (analytical HPLC: 4.6 mm×25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min); ¹ H NMR (300 MHz, DMSO-d₆) δ 8.26 (bt, 1H), 7.86 (m, 4H), 5.01 (m, 1H), 3.96 (t, J=6.6 Hz, 1H), 3.56 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H, coincident with m, 1H), 3.18 (m, 2H), 2.53 (s, 3H, coincident with m, 1H, DMSO-d₅), 2.54 (s, 3H), 2.36 (dd, J=14.6, 7.0 Hz, 1H), 2.32 (s, 3H), 1.74 (s, 3H); MS (ESI): m/e 507.3 (M+H)⁺.

Part C: N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid (Enzymatic Hydrolysis)

To a solution of methyl N² -(3,5-dimethylisoxazole-4-sulfonyl-N³ [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate HOAc salt (1.866 g, 3.29 mmol) in 0.4 N Hepes buffer (pH 7.1, 220 mL, 15 mmol) was added rabbit liver esterase (3.6 M crystalline suspension in ammonium sulfate, 2000 units, Sigma). The resulting solution was incubated at 37° C. for 60 hours. Protein was removed from the reaction mixture by ultra filtration (Amicon YM-10 membrane), and the filtrate was then concentrated in vacuo and lyophilized. Purification using a reverse phase silica column (5×9.5 cm in water; crude product loaded as an aqueous solution followed by elution with water (1200 mL) and by 500 mL each of 5, 10, 20 and 30% CH₃ CN-H₂ O. Fractions containing the desired product were pooled, acetonitrile was removed and the aqueous solution lyophilized to yield 1.5 g (93%) of pure zwitterion; ¹ H NMR (300 MHz, DMSO-d₆) δ 7.93 (t, 1H), 7.76 (s, 4H), 4.98 (m, 1H), 3.17-3.50 (m, 5H, coincident with water), 2.66 (dd, 1H), 2.56 (s, 3H), 2.35 (s, 3H), 2.36 (dd, 1H); MS (ESI): m/e 493.3 (M+H)⁺.

Part D: N² -(3,5-Dimethylisoxazole-4-sulfonyl)-N³ [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid Methanesulfonic Acid Salt

To a solution of the zwitterion (2.75 g, 5.43 mmol) in 50% CH₃ CN--H₂ O (135 mL) was added methanesulfonic acid (0.57 g, 5.97 mmol). The reaction mixture was stirred at room temperature for 1 h, resulting in a clear solution. Solvents were removed in vacuo and the residue placed under vacuum for several hours. The crude mesylate was dissolved in hot acetone and water until the solution was clear (120 mL total volume). After hot filtration the solution was allowed to cool slowly and was then refrigerated for 24 h. The resulting white precipitate was filtered and dried under vacuum, affording 1.72 g (52%) of the title compound; ¹ H NMR (300 MHz, DMSO-d₆) δ 9.37 (bs, 2H), 9.03 (bs, 2H), 8.57 (d, J=9.5 Hz, 1H), 8.23 (t, J=5.9 Hz, 1H), 7.88 (s, 4H), 5.03 (m, 1H), 3.91 (m, 2H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 1H), 3.21 (dd, J=17.6, 7.7 Hz, 1H), 3.09 (m, 1H), 2.58 (dd, J=14.6, 6.6 Hz, 1H), 2.54 (s, 3H), 2.38 (dd, J=14.6, 7.3 Hz, 1H), 2.33 (s, 3H, MsOH); MS (ESI): m/e 493.2 (M+H)⁺ ; Anal. Calcd. for C₂₁ H₂₈ N₆ O₁₀ S₂ : C, 42.85; H, 4.79; N, 14.05; S, 10.89. Found: C, 42.45; H, 4.74; N, 14.05; S, 11.19.

EXAMPLE 2420 Methyl N² -n-butyloxycarbonyl-N³ -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl)-(S)-2,3-diaminopropionate TFA salt

¹ HNMR (CDCl₃) δ 7.38 (1H, brd), 6.95 (1H, brd), 5.65 (1H, m), 4.98 (1H, m), 4.42 (1H, m),4.06 (2H, m), 3.76 (3H, s), 3.65 (2H, m), 3.48 (2H, m), 3.25 (2H, m), 2.95 (2H, m), 2.4 (2H, m), 1.95 (2H, brd), 1.6 (5H, m), 1.48 (2H, m), 1.35 (4H, m), 0.94 (3H, m) ppm; ESI mass spectrum 441 (M+H)⁺ free base

EXAMPLE 2421 Methyl N² -p-toluenesulfonyl-N³ -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionate TFA salt

¹ HNMR (CDCl₃) δ: 7.8 (1H, m), 7.68 (2H, m), 7.3 (3H, m), 5.7 (1H, m), 4.92 (1H, m), 4.1 (1H, m), 4.0 (1H, m), 3.7 (2H, m), 3.55 (3H, s), 3.45 (3H, m), 2.9 (2H, brd), 2.4 (3H, s), 2.38 (2H, m), 1.9 (3H, m), 1.65 (2H, m), 1.54 (2H, m), 1.35 (2H, m) ppm; ESI mass spectrum 495.3 (M+H)⁺ free base.

EXAMPLE 2422 N² -p-toluenesulfonyl-N³ -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionic acid TFA salt

¹ HNMR (CD₃ OD) δ: 7.7 (2H, m), 7.32 (2H, m), 4.85 (1H m), 4.1 (1H, m), 3.75 (1H, m), 3.65 (2H, m), 3.32 (3H, m), 3.2 (2H, m), 2.9 (2H, m), 2.4 (5H, m), 1.95 (2H, m), 1.62 (3H, m), 1.35 (4H, m),ppm; ESI mass spectrum 481.3 (M+H)⁺ free base

EXAMPLE 2423 N² -n-butyloxycarbonyl-N³ -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionic acid TFA salt

¹ HNMR (CD₃ OD) δ: 4.92 (1H, m), 4.3 (1H.sub., m), 4.05 (2H, m), 3.6 (2H, m), 3.38 (3H, m), 3.15 (1H, m), 2.95 (2H, m), 2.35 (2H, m), 1.95 (2H, m), 1.6 (5H, m), 1.35 (6H, m), 0.95 (3H, m) ppm; ESI mass spectrum 427.3 (M+H)⁺ free base.

EXAMPLE 2500 Methyl N³ -Boc-(S)-2,3-diaminopropionate

Part A: Methyl N² -Cbz-L-2,3-diaminopropionate HCl Salt

To a solution of N² -Cbz-L-2,3-diaminopropionic acid (Bachem, 220 g, 0.923 mol) in MeOH (2 L) at 0° C. was added thionyl chloride (76 mL, 1.04 mol) over 20 min. The solution was warmed to room temperature overnight (18 h) and then concentrated to give a solid. The solid was crystallized from CHCl₃ -MeOH to give 172 g (64%) of the desired ester; ¹ H NMR (DMSO-d₆) δ 8.38 (b, 3H), 7.96 (d, 1H), 7.38 (m, 5H), 5.05 (s, 2H), 4.44 (m, 1H), 3.66 (s, 3H), 3.14 (m, 2H).

Part B: Methyl N² -Cbz-N³ -Boc-L-2,3-diaminopropionate

To a solution of methyl N² -Cbz-(S)-2,3-diaminopropionate HCl salt (172 g, 0.596 mol) and di-tert-butyl dicarbonate (129.05 g, 0.591 mol) in CH₂ Cl₂ (2 L) cooled in an ice bath was added a saturated solution of NaHCO₃ (1200 mL, 0.96 mol) and the solution was warmed to room temperature overnight (18 h). The layers were separated and the aqueous washed with CH₂ Cl₂ (2×500 mL). The combined organic was washed with brine, dried (MgSO₄), and concentrated. The resulting white solid was triturated with hexanes (3×500 mL) and dried under vacuum, giving 195.99 g (93%) of the desired material; ¹ H NMR (DMSO-d₆): δ 7.60 (d, 1H), 7.35 (m, 5H), 6.88 (t, 1H), 5.02 (s, 2H), 4.14 (m, 1H), 3.60 (s, 3H), 3.28 (m, 2H), 1.37 (s, 9H).

Part C: Methyl N³ -Boc-(S)-2,3-diaminopropionate

To a solution of methyl N² -Cbz-N³ -Boc-(S)-2,3-diaminopropionate. (54.7 g, 0.155 mol) in EtOH (300 mL) was added 10% Pd/C (4.0 g). The mixture was placed on a Parr apparatus and hydrogenated at 50 p.s.i. overnight (18 h). The catalyst was filtered through Celite®, the filter cake washed with EtOH (3×50 mL) and the filtrate was concentrated in vacuo and placed under vacuum to give 32.63 g (96%) of the free base amine as a golden, viscous liquid; ¹ H NMR (DMSO-d₆): δ 8.20 (s, 1H), 6.90 (t, 1H), 5.36 (b, 3H), 3.61 9s, 3H), 3.51 (t, 1H), 3.18 (t, 2H), 1.38 (s, 9H).

EXAMPLE 2502 Resolution of 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic acid by Crystallization

3-(4-Cyanophenyl)isoxazolin-5(S)-ylacetic acid (127 g, 0.55 moles) and (+)-cinchonidine (180.37 g, 0.55 mol) were added to acetone (2.0 L) and stirred at ambien temperature for at least 1.5 hrs. The resulting precipitate (169.21 g) was collected by filtration. The precipitate was dissolved in hot acetone (4.0 L) while stirring. After complete dissolution, the solution was allowed to stand overnight. The crystals formed were collected by filtration and recrystallized with acetone gain to yield the 3-(4-cyanophenyl)isoxazolin-5(S)-lacetic acid/(+)-cinchonidine salt in 33% overall yield and >99 % diastereomeric excess. The 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid was liberated from its cinchonidine salt complex by suspending the salt in ethereal HCL (1 N), filtering the solid after equilibration and evaporating the ether solution to provide the solid 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid. The R-isomer could be obtained from the mother liquor. Other chiral bases used include ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.

EXAMPLE 2503 General Procedure for the Preparation of Compounds of the Formula (Ie) and (If)

Part A.

Z-2,3-diaminopropionic acid (2.5 g, Fluka) was combined with Fmoc-N-Hydroxysuccinimide (1.1 eq., 3.89 g) and NaHCO₃ (3 eq., 2.65 g), in dioxane (24 ml) and H₂ O (21 ml). After stirring at room temperature overnight, the pH was adjusted with Na₂ CO₃ to pH 9. The solution was extracted three times with ethyl ether, then the aqueous layer was acidified with conc. HCl, with stirring. At pH 4-5, a solid precipitated out. This was filtered, rinsed with 1 N HCl, and dried. (93% yield)

Part B.

Wang resin (2.0 g, 1.16 mmole/g, Advanced Chem Tech) was added to triphenylphosphine (5 eq, 3.0 g) in 20 ml DMF. CBr₄ (5 eq, 3.85 g) was then added and the solution was stirred at room temperature 3 hours. The resin was filtered and rinsed with DMF. Fmoc-Z-2,3-diaminopropionic acid (1.60 g, 1.5 equiv.) was dissolved in 20 ml DMF and the above resin was added, with 1.5 equiv. DIEA (0.60 ml) and 1.0 equiv. CsI (0.60 g) and stirred at room temperature overnight. The resin was filtered and rinsed with DMF and MeOH. Weight gain, IR, elemental analysis, and picric acid determination were used to establish the substitution level of the resin as approx. 0.8 mmole/g.

Part C.

The above derivatized resin (150 mg) was deprotected by mixing 10 min. with 20% piperidine/DMF. of The Fmoc-isoxazolin derivative (1.5 eq., 0.18 mmole) was dissolved in 1.5 ml DMF and added to the resin with HBTU (1.5 eq, 68 mg) and DIEA (1.5 eq, 32 ul). The tubes were mixed overnight, then drained, rinsed with DMF and MeOH, and the resin split into two portions. One portion was deprotected with 20% piperidine/DMF and then cleaved to produce the primary amine analogs. The other portion was deprotected with 20% piperidine/DMF and then coupled overnight with bis Boc-S-ethyl isothiourea (2 eq., 37 mg) and DEA (2 eq., 21 ul) in DMF.

Part D.

After rinsing, the compounds were cleaved from the resin by mixing with 1:1 TFA:CH₂ Cl₂ for two hours. The filtrate was rotovapped under reduced pressure to an oil, dissolved in 1:1 acetonitrile:H₂ O, and lyophilized. The crude material was analyzed by mass spec and HPLC. They were then purified by reverse phase HPLC (ACN:H₂ O:0.1% TFA, C 18 column).

Using the above methods and variations thereof known in the art of organic synthesis, the additional examples in Tables 1-2, 2A-2D, 3-14 can be prepared.

                                      TABLE 1                                      __________________________________________________________________________                                       (V)                                           ##STR65##                                                                     Ex.                                                                            No.                                                                               R.sup.2                                                                           R.sup.4 Y              n R.sup.14                                                                           n'                                          __________________________________________________________________________      1 H  H       OH             2 H   0                                            2 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             2 H   0                                            3 H  NHSO.sub.2 CH.sub.2 Ph                                                                 OH             2 H   0                                            4 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OH             2 H   0                                            5 H  NHCOnC.sub.4 H.sub.9                                                                   OH             2 H   0                                            6 H  H       OH             1 H   1                                            7 H  H       OH             1 H   0                                            8 H  H       OH             2 H   1                                            9 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             1 H   1                                           10 H  NHSO.sub.2 CH.sub.2 Ph                                                                 OH             1 H   1                                           11 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OH             1 H   1                                           12 H  NHCOnC.sub.4 H.sub.9                                                                   OH             1 H   1                                           13 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            OMe            2 H   0                                           14 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OMe            2 H   0                                           15 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            CMe            1 H   1                                           16 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OMe            1 H   1                                           17 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            OEt            2 H   0                                           18 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OEt            2 H   0                                           19 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                            OEt            1 H   1                                           20 H  NHCO.sub.2 CH.sub.2 Ph                                                                 OEt            1 H   1                                           21 Boc                                                                               NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             2 H   0                                           22 Boc                                                                               NHCO.sub.2 CH.sub.2 Ph                                                                 OH             2 H   0                                           23 Boc                                                                               NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             1 H   1                                           24 Boc                                                                               NHCO.sub.2 CH.sub.2 Ph                                                                 OH             1 H   1                                           25 Cbz                                                                               NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             2 H   0                                           26 Cbz                                                                               NHCO.sub.2 CH.sub.2 Ph                                                                 OH             2 H   0                                           27 Cbz                                                                               NHSO.sub.2 nC.sub.4 H.sub.9                                                            OH             1 H   1                                           28 Cbz                                                                               NHCO.sub.2 CH.sub.2 Ph                                                                 OH             1 H   1                                           29 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                             ##STR66##     2 H   0                                           30 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                             ##STR67##     2 H   0                                           31 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                             ##STR68##     2 H   0                                           32 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                             ##STR69##     2 H   0                                           31 H  NHSO.sub.2 nC.sub.4 H.sub.9                                                             ##STR70##     2 H   0                                           33 H  H       OH             2 CO.sub.2 Me                                                                        0                                           34 H  H       OMe            2 H   0                                           35 H  NHSO.sub.2 CH.sub.2 Ph                                                                 OMe            2 H   0                                           36 H  NHCOnC.sub.4 H.sub.9                                                                   OMe            2 H   0                                           37 H  H       OMe            1 H   1                                           38 H  H       OMe            1 H   0                                           39 H  H       OMe            2 H   1                                           40 H  NHSO.sub.2 CH.sub.2 Ph                                                                 OMe            1 H   1                                           41 H  NHCOnC.sub.4 H.sub.9                                                                   OMe            1 H   1                                           42 H  H       OMe            2 CO.sub.2 Me                                                                        0                                           __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________                                            (VI)                                     ##STR71##                                                                     Example                              MS                                        Number                                                                              R.sup.2                                                                           R.sup.8       Y              (M + H).sup.+                             __________________________________________________________________________      43  H  Ph            OH             412                                        .sup.  43A                                                                         H  Ph            OH             HNMR                                       44  H                                                                                  ##STR72##    OH                                                        45  H                                                                                  ##STR73##    OH                                                        46  H                                                                                  ##STR74##    OH                                                        47  H                                                                                  ##STR75##    OH                                                        48  H                                                                                  ##STR76##    OH                                                        49  H                                                                                  ##STR77##    OH                                                        50  H                                                                                  ##STR78##    OH                                                        51  H                                                                                  ##STR79##    OH                                                        52  H                                                                                  ##STR80##    OH                                                        53  H                                                                                  ##STR81##    OH                                                        54  H                                                                                  ##STR82##    OH                                                        55  H                                                                                  ##STR83##    OH                                                        56  H                                                                                  ##STR84##    OH                                                        57  H                                                                                  ##STR85##    OH                                                        58  H                                                                                  ##STR86##    OH                                                        59  H                                                                                  ##STR87##    OH                                                        60  H                                                                                  ##STR88##    OH                                                        61  H                                                                                  ##STR89##    OH                                                        62  H                                                                                  ##STR90##    OH                                                        63  H                                                                                  ##STR91##    OH                                                        64  H                                                                                  ##STR92##    OH                                                        65  H                                                                                  ##STR93##    OH                                                        66  H                                                                                  ##STR94##    OH                                                        67  H                                                                                  ##STR95##    OH                                                        68  H                                                                                  ##STR96##    OH                                                        69  H  Et            OH                                                        70  H  n-Pr          OH                                                        71  H  --C.tbd.CH    OH                                                        72  H  CO.sub.2 H    OH                                                        73  H  CH.sub.2 Ph   OH                                                        74  H  CH.sub.2 CH.sub.2 Ph                                                                         OH                                                        75  H  --C═CH.sub.2                                                                             OH                                                        76  H                                                                                  ##STR97##    OH                                                        80  Cbz                                                                               Ph            OH                                                        81  Cbz                                                                                ##STR98##    OH                                                        82  Boc                                                                               Ph            OH                                                        83  Boc                                                                                ##STR99##    OH                                                        84  H                                                                                  ##STR100##                                                                                   ##STR101##                                               85  H                                                                                  ##STR102##                                                                                   ##STR103##                                               86  H                                                                                  ##STR104##                                                                                   ##STR105##                                               87  H                                                                                  ##STR106##                                                                                   ##STR107##                                               88  H                                                                                  ##STR108##                                                                                   ##STR109##                                               89  H  Ph            OMe                                                       90  H                                                                                  ##STR110##   OMe                                                       91  H                                                                                  ##STR111##   OMe                                                       92  H                                                                                  ##STR112##   OMe                                                       93  H                                                                                  ##STR113##   OMe                                                       94  H                                                                                  ##STR114##   OMe                                                       95  H                                                                                  ##STR115##   OMe                                                       96  H                                                                                  ##STR116##   OMe                                                       97  H                                                                                  ##STR117##   OMe                                                       98  H                                                                                  ##STR118##   OMe                                                       99  H                                                                                  ##STR119##   OMe                                                      100  H                                                                                  ##STR120##   OMe                                                      101  H                                                                                  ##STR121##   OMe                                                      102  H                                                                                  ##STR122##   OMe                                                      103  H                                                                                  ##STR123##   OMe                                                      104  H                                                                                  ##STR124##   OMe                                                      105  H                                                                                  ##STR125##   OMe                                                      106  H                                                                                  ##STR126##   OMe                                                      107  H                                                                                  ##STR127##   OMe                                                      108  H                                                                                  ##STR128##   OMe                                                      109  H                                                                                  ##STR129##   OMe                                                      110  H                                                                                  ##STR130##   OMe                                                      111  H                                                                                  ##STR131##   OMe                                                      112  H                                                                                  ##STR132##   OMe                                                      113  H                                                                                  ##STR133##   OMe                                                      114  H                                                                                  ##STR134##   OMe                                                      115  H  Et            OMe            361                                       116  H  n-Pr          OMe                                                      117  H  --C.tbd.H     OMe                                                      118  H  CO.sub.2 H    OMe                                                      119  H  CH.sub.2 Ph   OMe            423                                       120  H  CH.sub.2 CH.sub.2 Ph                                                                         OMe            437                                       121  H  --C═CH.sub.2                                                                             OMe                                                      122  H                                                                                  ##STR135##   OMe                                                      126  Cbz                                                                               Ph            OMe                                                      127  Cbz                                                                                ##STR136##   OMe                                                      128  Boc                                                                               Ph            OMe                                                      129  Boc                                                                                ##STR137##   OMe                                                      130  H  Ph            OEt                                                      131  H                                                                                  ##STR138##   OEt                                                      132  H                                                                                  ##STR139##   OEt                                                      133  H                                                                                  ##STR140##   OEt                                                      134  H                                                                                  ##STR141##   OEt                                                      135  H                                                                                  ##STR142##   OEt                                                      136  H                                                                                  ##STR143##   OEt                                                      137  H                                                                                  ##STR144##   OEt                                                      138  H                                                                                  ##STR145##   OEt                                                      139  H                                                                                  ##STR146##   OEt                                                      140  H                                                                                  ##STR147##   OEt                                                      141  H                                                                                  ##STR148##   OEt                                                      142  H                                                                                  ##STR149##   OEt                                                      143  H                                                                                  ##STR150##   OEt                                                      144  H                                                                                  ##STR151##   OEt                                                      145  H                                                                                  ##STR152##   OEt                                                      146  H                                                                                  ##STR153##   OEt                                                      147  H                                                                                  ##STR154##   OEt                                                      148  H                                                                                  ##STR155##   OEt                                                      149  H                                                                                  ##STR156##   OEt                                                      150  H                                                                                  ##STR157##   OEt                                                      151  H                                                                                  ##STR158##   OEt                                                      152  H                                                                                  ##STR159##   OEt                                                      153  H                                                                                  ##STR160##   OEt                                                      154  H                                                                                  ##STR161##   OEt                                                      155  H                                                                                  ##STR162##   OEt                                                      156  H  Et            OEt                                                      157  H  n-Pr          OEt                                                      158  H  --C═H     OEt                                                      159  H  CO.sub.2 H    OEt                                                      160  H  CH.sub.2 Ph   OEt                                                      161  H  CH.sub.2 CH.sub.2 Ph                                                                         OEt                                                      162  H  --C.tbd.CH.sub.2                                                                             OEt                                                      163  H                                                                                  ##STR163##   OEt                                                      164  H  CH.sub.2 N(Me)Ph                                                                             OEt                                                      165  H  CH.sub.2 NEt.sub.2                                                                           OEt                                                      166  H  CH.sub.2 NMe.sub.2                                                                           OEt                                                      167  Cbz                                                                               Ph            OEt                                                      168  Cbz                                                                                ##STR164##   OEt                                                      169  Boc                                                                               Ph            OEt                                                      170  Boc                                                                                ##STR165##   OEt                                                      338  H  CO.sub.2 Me   OMe            mp 160°                            339  H  CO.sub.2 Me   H              363                                       340  H  CONMe.sub.2   OMe            404                                       341  H                                                                                  ##STR166##   OMe            524                                       343  H  n-butyl       OH                                                       344  H  n-butyl       OMe            389                                       345  H  n-butyl       OEt                                                      346  H  isobutyl      OH                                                       347  H  isobutyl      OMe            389                                       348  H  isobutyl      OEt            403                                       349  H  CH.sub.2 SPh  OH                                                       350  H  CH.sub.2 SPh  OMe            455                                       351  H  CH.sub.2 SPh  OEt                                                      352  H  CH.sub.2 OPh  OH                                                       353  H  CH.sub.2 OPh  OMe                                                      354  H  CH.sub.2 OPh  OEt                                                      355  H  CH.sub.2 SO.sub.2 Ph                                                                         OH                                                       356  H  CH.sub.2 SO.sub.2 Ph                                                                         OMe                                                      357  H  CH.sub.2 SO.sub.2 Ph                                                                         OEt                                                      358  H  CH.sub.2 NHSO.sub.2 Ph                                                                       OH                                                       359  H  CH.sub.2 NHSO.sub.2 Ph                                                                       OMe            502                                       360  H  CH.sub.2 NHSO.sub.2 Ph                                                                       OEt                                                      361  H  CH.sub.2 NHSO.sub.2 n-Bu                                                                     OH                                                       362  H  CH.sub.2 NHSO.sub.2 n-Bu                                                                     OMe            482                                       363  H  CH.sub.2 NHSO.sub.2 n-Bu                                                                     OEt                                                      364  H  CH.sub.2 COOH OH             377                                       365  H  CH.sub.2 COOMe                                                                               OMe            405                                       366  H  CH.sub.2 COOEt                                                                               OEt                                                      367  H  CH.sub.2 CH.sub.2 COOH                                                                       OH                                                       368  H  CH.sub.2 CH.sub.2 COOMe                                                                      OMe            419                                       369  H  CH.sub.2 CH.sub.2 COOEt                                                                      OEt                                                      370  H  CH.sub.2 NMe.sub.2                                                                           OH                                                       371  H  CH.sub.2 NMe.sub.2                                                                           OMe            390                                       372  H  CH.sub.2 NMe.sub.2                                                                           OEt                                                      434  BOC                                                                               --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                                              OtBu           622                                       435  H  --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                                              OH             466                                       439  H  --C(═O)OC.sub.2 H.sub.5                                                                  OEt            419                                       441  H                                                                                  ##STR167##   OH             484                                       446  H  (CH.sub.2).sub.3 Ph                                                                          OMe                                                      447  H  CH.sub.2 -(2-pyr)                                                                            OMe                                                      448  H  (CH.sub.2).sub.2 -(2-pyr)                                                                    OMe                                                      449  H  (CH.sub.2).sub.2 -(3-pyr)                                                                    OMe            438                                       450  H  (CH.sub.2).sub.2 -(4-pyr)                                                                    OMe            438                                       452  H  --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                                              OMe            480                                       453  BOC                                                                                ##STR168##   OMe            635                                       454  H  C(═O)N(CH.sub.3)--                                                                       OMe                                                              (CH.sub.2).sub.2 C.sub.6 H.sub.5                                       455  H                                                                                  ##STR169##   OMe                                                      456  H  i-hexyl       OEt            431                                       457  H  --C.tbd.CSiMe.sub.3                                                                          OMe            429                                       458  H  --(CH.sub.2).sub.2 -(3-pyr)                                                                  OH             424                                       459  H  --(CH.sub.2).sub.2 -(2-pyr)                                                                  OH             424                                       460  H  --(CH.sub.2).sub.3 --C.sub.6 H.sub.5                                                         OH             437                                       461  H  --(CH.sub.2).sub.3 --C.sub.6 H.sub.5                                                         OMe            451                                       462  H                                                                                  ##STR170##   OEt            538                                       463  H                                                                                  ##STR171##   OH             510                                       464  H                                                                                  ##STR172##   OMe            492                                       465  H                                                                                  ##STR173##   OMe            492                                       466  H                                                                                  ##STR174##   OMe            510                                       467  H                                                                                  ##STR175##   OMe            510                                       468  H                                                                                  ##STR176##   OMe            462                                       469  H                                                                                  ##STR177##   OMe            448                                       587  H  --(CH.sub.2).sub.3 -(4-pyr)                                                                  OH             424                                       611  H  --CH.sub.2 NHSO.sub.2 NMe.sub.2                                                              OMe            469                                       612  H                                                                                  ##STR178##   OMe            416                                       __________________________________________________________________________

                                      TABLE 2A                                     __________________________________________________________________________     Example                          MS                                            Number                                                                              R.sup.1 -V   R.sup.16   Y   (M + H).sup.+                                 __________________________________________________________________________     275  4-amidinophenyl                                                                             H          OH  334                                           276  4-amidinophenyl                                                                             benzyloxycarbonyl                                                                         OH  468                                           277  4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                        OH                                                278  4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                        OH  434                                           278a 4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                        OMe 448                                           278b 4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                        OH  434                                           279  4-amidinophenyl                                                                             ethyloxycarbonyl                                                                          OH                                                280  4-amidinophenyl                                                                             methyloxycarbonyl                                                                         OH                                                290  4-amidinophenyl                                                                             phenylethylcarbonyl                                                                       OH  510                                           291  4-amidinophenyl                                                                             2,2-dimethyl-                                                                             OH                                                                  propyl carbonyl                                              292  4-amidinophenyl                                                                             n-pentylcarbonyl                                                                          OH                                                293  4-amidinophenyl                                                                             n-butylcarbonyl                                                                           OH                                                294  4-amidinophenyl                                                                             propionyl  OH                                                295  4-amidinophenyl                                                                             acetyl     OH                                                296  4-amidinophenyl                                                                             methylsulfonyl                                                                            OH                                                297  4-amidinophenyl                                                                             ethylsulfonyl                                                                             OH                                                298  4-amidinophenyl                                                                             n-butylsulfonyl                                                                           OH                                                299  4-amidinophenyl                                                                             phenylsulfonyl                                                                            OH  474                                           300  4-amidinophenyl                                                                             4-methylphenyl-                                                                           OH  488                                                             sulfonyl                                                     301  4-amidinophenyl                                                                             benzylsulfonyl                                                                            OH                                                302  4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                         OH                                                303  4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                         OH                                                304  4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                         OH                                                305  4-amidinophenyl                                                                             2-pyridylmethyl-                                                                          OH                                                                  carbonyl                                                     306  4-amidinophenyl                                                                             3-pyridylmethyl                                                                           OH                                                                  carbonyl                                                     307  4-amidinophenyl                                                                             4-pyridylmethyl-                                                                          OH                                                                  carbonyl                                                     308  4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                         OH                                                                  carbonyl                                                     309  4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                         OH                                                                  carbonyl                                                     310  4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                         OH                                                                  carbonyl                                                     311  4-amidinophenyl                                                                             H          OMe                                               312  4-amidinophenyl                                                                             benzyloxycarbonyl                                                                         OMe 482                                           313  4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                        OMe                                               314  4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                        OMe 448                                           315  4-amidinophenyl                                                                             ethyloxycarbonyl                                                                          OMe                                               316  4-amidinophenyl                                                                             methyloxycarbonyl                                                                         OMe                                               317  4-amidinophenyl                                                                             phenylethylsulfonyl                                                                       OH  502                                           318  4-amidinophenyl                                                                             2,2-dimethyl-                                                                             OMe                                                                 propylcarbonyl                                               319  4-amidinophenyl                                                                             n-pentylcarbonyl                                                                          OMe                                               320  4-amidinophenyl                                                                             n-butylcarbonyl                                                                           OMe                                               321  4-amidinophenyl                                                                             propionyl  OMe                                               322  4-amidinophenyl                                                                             acetyl     OMe                                               323  4-amidinophenyl                                                                             methylsulfonyl                                                                            OMe 426                                           324  4-amidinophenyl                                                                             ethylsulfonyl                                                                             OMe 440                                           325  4-amidinophenyl                                                                             n-butylsulfonyl                                                                           OMe                                               326  4-amidinophenyl                                                                             phenylsulfonyl                                                                            OMe 488                                           327  4-amidinophenyl                                                                             4-methylphenyl-                                                                           OMe 502                                                             sulfonyl                                                     328  4-amidinophenyl                                                                             benzylsulfonyl                                                                            OMe 502                                           329  4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                         OMe                                               330  4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                         OMe                                               331  4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                         OMe                                               332  4-amidinophenyl                                                                             2-pyridylmethyl-                                                                          OMe                                                                 carbonyl                                                     333  4-amidinophenyl                                                                             3-pyridylmethyl-                                                                          OMe                                                                 carbonyl.                                                    334  4-amidinophenyl                                                                             4-pyridylmethyl-                                                                          OMe                                                                 carbonyl                                                     335  4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                         OMe                                                                 carbonyl                                                     336  4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                         OMe                                                                 carbonyl                                                     337  4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                         OMe                                                                 carbonyl                                                     374                                                                                  ##STR179##  benzyloxycarbonyl                                                                         OMe 475                                           440  4-(BOCamidino)phenyl                                                                        benzyloxycarbonyl                                                                         OMe 582                                           442  4-(BOCamidino)phenyl                                                                        n-butyloxycarbonyl                                                                        OMe 594                                           443  4-amidinophenyl                                                                             1-naphthylsulfonyl                                                                        OMe 538                                           444  4-amidinophenyl                                                                             2-naphthylsulfonyl                                                                        OMe 538                                           445  4-amidinophenyl                                                                             styrylsulfonyl                                                                            OMe 514                                           445a 4-amidinophenyl                                                                             styrylsulfonyl                                                                            OH  500                                           451                                                                                  ##STR180##  n-butyloxycarbonyl                                                                        OMe 441                                           471  4-amidinophenyl                                                                             4-butyloxyphenyl-                                                                         OMe 560                                                             sulfonyl                                                     472  4-amidinophenyl                                                                             2-thienylsulfonyl                                                                         OMe 494                                           473  4-amidinophenyl                                                                             3-methylphenyl-                                                                           OMe 502                                                             sulfonyl                                                     474  4-amidinophenyl                                                                             4-iodophenyl                                                                              OMe 614                                           475  4-amidinophenyl                                                                             3-trifluoromethyl-                                                                        OMe 556                                                             phenylsulfonyl                                               476  4-amidinophenyl                                                                             3-chlorophenyl-                                                                           OMe 522                                                             sulfonyl                                                     477  4-amidinophenyl                                                                             2-methoxycarbonyl-                                                                        OMe 546                                                             phenylsulfonyl                                               478  4-amidinophenyl                                                                             2,4,6-trimethyl-                                                                          OMe 530                                                             phenylsulfonyl                                               478a 4-amidinophenyl                                                                             2,4,6-trimethyl-                                                                          OH  516                                                             phenylsulfonyl                                               479  4-amidinophenyl                                                                             2-chlorophenyl-                                                                           OMe 522                                                             sulfonyl                                                     479a 4-amidinophenyl                                                                             2-chlorophenyl-                                                                           OH  508                                                             sulfonyl                                                     480  4-amidinophenyl                                                                             2-trifluoromethyl-                                                                        OMe 556                                                             phenylsulfonyl                                               481  4-amidinophenyl                                                                             4-trifluoromethyl-                                                                        OMe 556                                                             phenylsulfonyl                                               482  4-amidinophenyl                                                                             2-fluorophenyl-                                                                           OMe 506                                                             sulfonyl                                                     483  4-amidinophenyl                                                                             4-fluorophenyl-                                                                           OMe 506                                                             sulfonyl                                                     484  4-amidinophenyl                                                                             4-methoxyphenyl-                                                                          OMe 518                                                             sulfonyl                                                     485  4-amidinophenyl                                                                             2,3,5,6-tetramethyl-                                                                      OMe 544                                                             phenylsulfonyl                                               485a 4-amidinophenyl                                                                             2,3,5,6-tetramethyl-                                                                      OH  530                                                             phenylsulfonyl                                               486  4-amidinophenyl                                                                             4-cyanophenyl-                                                                            OMe 513                                                             sulfonyl                                                     487  4-amidinophenyl                                                                             4-chlorophenyl-                                                                           OMe 522                                                             sulfonyl                                                     488  4-amidinophenyl                                                                             4-ethylphenyl-                                                                            OMe 516                                                             sulfonyl                                                     489  4-amidinophenyl                                                                             4-propylphenyl-                                                                           OMe 530                                                             sulfonyl                                                     490  4-amidinophenyl                                                                             n-propylsulfonyl                                                                          OMe 454                                           490a 4-amidinophenyl                                                                             n-propylsulfonyl                                                                          OH  440                                           491  4-amidinophenyl                                                                             2-phenylethyl-                                                                            OMe 516                                                             sulfonyl                                                     492  4-amidinophenyl                                                                             4-isopropylphenyl-                                                                        OMe 530                                                             sulfonyl                                                     492a 4-amidinophenyl                                                                             4-isopropylphenyl-                                                                        OH  516                                                             sulfonyl                                                     493  4-amidinophenyl                                                                             3-phenylpropyl-                                                                           OMe 530                                                             sulfonyl                                                     494  4-amidinophenyl                                                                             3-pyridylsulfonyl                                                                         OMe 489                                           495  4-amidinophenyl                                                                             2-pyridylsulfonyl                                                                         OMe 489                                           496  4-amidinophenyl                                                                             2,2-diphenyl-1-                                                                           OMe 590                                                             ethenylsulfonyl                                              497  4-amidinophenyl                                                                             2-pyrimidinyl-                                                                            OMe                                                                 sulfonyl                                                     498  4-amidinophenyl                                                                             4-methyl-2-                                                                               OMe                                                                 pyrimidinylsulfonyl                                          499  4-amidinophenyl                                                                             4,6-dimethyl-2-                                                                           OMe                                                                 pyrimidinylsulfonyl                                          500  4-amidinophenyl                                                                             1,2,4-triazol-3-                                                                          OMe                                                                 ylsulfonyl                                                   501  4-amidinophenyl                                                                             1-methyl-1,3,4-                                                                           OMe                                                                 triazol-5-ylsulfonyl                                         502  4-amidinophenyl                                                                             3,5-dimethyl-4-                                                                           OMe                                                                 pyrazolylsulfonyl                                            503  4-amidinophenyl                                                                             1-phenyl-4-                                                                               OMe                                                                 pyrazolylsulfonyl                                            504  4-amidinophenyl                                                                             n-butylaminosulfonyl                                                                      OMe 483                                           505  4-amidinophenyl                                                                             i-butylaminosulfonyl                                                                      OMe 483                                           506  4-amidinophenyl                                                                             t-butylaminosulfonyl                                                                      OMe 483                                           507  4-amidinophenyl                                                                             i-propylamino-                                                                            OMe 469                                                             sulfonyl                                                     508  4-amidinophenyl                                                                             cyclohexylamino-                                                                          OMe 509                                                             sulfonyl                                                     509  4-amidinophenyl                                                                             phenylaminosulfonyl                                                                       OMe 503                                           510  4-amidinophenyl                                                                             benzylaminosulfonyl                                                                       OMe 517                                           511  4-amidinophenyl                                                                             dimethylamino-                                                                            OMe 455                                                             sulfonyl                                                     512  4-amidino-2-fluoro-                                                                         3-methylphenyl-                                                                           OMe 520                                                phenyl       sulfonyl                                                     512A 4-amidino-2-fluoro-                                                                         3-methylphenylsulfonyl                                                                    OH  506                                                phenyl                                                                    514  2-amidino-5-pyridyl                                                                         3-methylphenyl-                                                                           OMe 503                                                             sulfonyl                                                     514A 2-amidino-5-pyridyl                                                                         3-methylphenylsulfonal                                                                    OH  489                                           516  3-amidino-6-pyridyl                                                                         3-methylphenyl-                                                                           OMe 503                                                             sulfonyl                                                     516A 3-amidino-6-pyridyl                                                                         3-methylphenylsulfonyl                                                                    OH  489                                           518  4-amidinophenyl                                                                             4-fluorophenylamino-                                                                      OMe 485                                                             carbonyl                                                     519  4-amidinophenyl                                                                             1-naphthylamino-                                                                          OMe 517                                                             carbonyl                                                     520  4-amidinophenyl                                                                             benzylaminocarbonyl                                                                       OMe                                               521  4-amidinophenyl                                                                             n-butylaminocarbonyl                                                                      OMe 435                                           522  4-amidinophenyl                                                                             4-ethylphenyl-                                                                            OMe 480                                                             carbonyl                                                     523  4-amidinophenyl                                                                             biphenylcarbonyl                                                                          OMe 528                                           524  4-amidinophenyl                                                                             2-naphthylcarbonyl                                                                        OMe 502                                           525  4-amidinophenyl                                                                             (2-chlorophenyl)                                                                          OMe 516                                                             methoxycarbonyl                                              526  4-amidinophenyl                                                                             (2-chlorophenyl)                                                                          OH  502                                                             methoxycarbonyl                                              527  4-amidinophenyl                                                                             (2-bromophenyl)                                                                           OMe 562                                                             methoxycarbonyl                                              528  4-ainidinophenyl                                                                            (2-bromophenyl)                                                                           OH  548                                                             methoxycarbonyl                                              528a 4-amidinophenyl                                                                             (2-bromophenyl)-                                                                          OH  516                                                             carbonyl                                                     529  4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                        OMe 476                                           530  4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                        OH  460                                           531  4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                       OMe 448                                           532  4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                       OH  434                                           533  4-amidinophenyl                                                                             2-cyclopropylethoxy-                                                                      OMe 460                                                             carbonyl                                                     534  4-amidinophenyl                                                                             2-cyclopropylethoxy-                                                                      OH  446                                                             carbonyl                                                     535  4-amidinophenyl                                                                             2-cyclopentylethoxy-                                                                      OMe 488                                                             carbonyl                                                     536  4-amidinophenyl                                                                             2-cyclopentylethoxy-                                                                      OH  474                                                             carbonyl                                                     537  4-amidinophenyl                                                                             4,4,4-trifluoro-                                                                          OMe 502                                                             butyloxycarbonyl                                             538  4-amidinophenyl                                                                             4,4,4-trifluoro-                                                                          OH  488.                                                            butyloxycarbonyl                                             539  4-amidinophenyl                                                                             n-propylsulfonyl                                                                          OMe                                               540  4-amidinophenyl                                                                             2-methylphenyl-                                                                           OH  452                                                             carbonyl                                                     540a 4-amidinophenyl                                                                             2-methylphenyl-                                                                           OH  488                                                             sulfonyl                                                     541  4-amidinophenyl                                                                             4-chloro-2,5-dimethyl-                                                                    OMe 550                                                             phenylsulfonyl                                               541a 4-amidinophenyl                                                                             4-chloro-2,5-dimethyl-                                                                    OMe 536                                                             phenylsulfonyl                                               542  4-amidinophenyl                                                                             2,3-dichlorophenyl-                                                                       OMe 556                                                             sulfonyl                                                     543  4-amidinophenyl                                                                             2-bromophenyl-                                                                            OMe 568                                                             sulfonyl                                                     544  4-amidinophenyl                                                                             3-bromophenyl-                                                                            OMe 568                                                             sulfonyl                                                     545  4-amidinophenyl                                                                             4-bromophenyl-                                                                            OMe 568                                                             sulfonyl                                                     546  4-amidinophenyl                                                                             biphenylsulfonyl                                                                          OMe 564                                           547  4-amidinophenyl                                                                             5-chloro-1,3-                                                                             OMe 540                                                             dimethyl-4-pyrazolyl                                         548  4-amidinophenyl                                                                             3-bromo-2- OMe 574                                                             thienylsulfonyl                                              549  4-amidinophenyl                                                                             5-bromo-2- OMe 574                                                             thienylsulfonyl                                              550  4-amidinophenyl                                                                             5-[1-methyl-5-                                                                            OMe 642                                                             trifluoromethyl-3-                                                             pyrazolyl]-2-                                                                  thienylsulfonyl                                              551  4-amidinophenyl                                                                             5-(3-isoxazolyl)-2-                                                                       OMe 561                                                             thienylsulfonyl                                              552  4-amidinophenyl                                                                             5-(2-pyridinyl)-2-                                                                        OMe 571                                                             thienylsulfonyl                                              553  4-amidinophenyl                                                                             4-methyl-2-                                                                               OMe 566                                                             methylcarbonylamino-5-                                                         thiazolylsulfonyl                                            554  4-amidinophenyl                                                                             2-benzothienyl-                                                                           OMe 628                                                             sulfonyl                                                     555  4-amidinophenyl                                                                             2-benzothienyl-                                                                           OMe 544                                                             sulfonyl                                                     556  4-amidinophenyl                                                                             3-methyl-2-                                                                               OMe 558                                                             benzothienylsulfonyl                                         557  4-amidinophenyl                                                                             8-quinolinylsulfonyl                                                                      OMe 539                                           558  4-amidinophenyl                                                                             8-quinolinylsulfonyl                                                                      OH  525                                           559  4-amidinophenyl                                                                             2,1,3-benzo-                                                                              OMe 546                                                             thiadiazol-4-ylsulfonyl                                      560  4-amidinophenyl                                                                             2,1,3-benzo-                                                                              OH  532                                                             thiadiazol-4-ylsulfonyl                                      561  4-amidinophenyl                                                                             4-N,N-dimethylamino-1-                                                                    OMe                                                                 naphthylsulfonyl                                             562  4-amidinophenyl                                                                             4-N,N-dimethylamino-1-                                                                    OH                                                                  naphthylsulfonyl                                             563  4-amidinophenyl                                                                             2,1,3-benzoxadiazol-4-                                                                    OMe                                                                 ylsulfonyl                                                   564  4-amidinophenyl                                                                             2,1,3-benzoxadiazol-4-                                                                    OH                                                                  ylsulfonyl                                                   565  4-amidinophenyl                                                                             2,2,5,7,8-pentamethyl                                                                     OMe                                                                 3,4-dihydro-2Hbenzo-                                                           pyran-6-ylsulfonyl                                           566  4-amidinophenyl                                                                             2,2,5,7,8-pentamethyl                                                                     OH                                                                  3,4-dihydro-2Hbenzo-                                                           pyran-6-ylsulfonyl                                           567  4-N-methylamidino                                                                           3-methylphenylsulfonyl                                                                    OMe                                                    phenyl                                                                    568  4-N-ethylamidino                                                                            3-methylphenylsulfonyl                                                                    OMe 530                                                phenyl                                                                    569  4-N-n-propylamidino                                                                         3-methylphenylsulfonyl                                                                    OMe                                                    phenyl                                                                    570  4-N-benzylamidino phenyl                                                                    3-methylphenylsulfonyl                                                                    OMe                                               571  4-N-n-butylamidino                                                                          3-methylphenylsulfonyl                                                                    OMe 558                                                phenyl                                                                    572  4-N-methylamidino                                                                           3-methylphenylsulfonyl                                                                    OH                                                     phenyl                                                                    573  4-N-ethylamidino                                                                            3-methylphenylsulfonyl                                                                    OH  516                                                phenyl                                                                    574  4-N-n-propylamidino                                                                         3-methylphenylsulfonyl                                                                    OH                                                     phenyl                                                                    575  4-N-benzylamidino                                                                           3-methylphenylsulfonyl                                                                    OH                                                     phenyl                                                                    576  4-N-n-butylamidino                                                                          3-methylphenylsulfonyl                                                                    OH  544                                                phenyl                                                                    577  4-N-methylamidino-                                                                          n-butyloxycarbonyl                                                                        OMe                                                    phenyl                                                                    578  4-N-ethylamidinophenyl                                                                      n-butyloxycarbonyl                                                                        OMe                                               579  4-N-npropylamidino-                                                                         n-butyloxycarbonyl                                                                        OMe                                                    phenyl                                                                    580  4-N-n-butylamidino-                                                                         n-butyloxycarbonyl                                                                        OMe 504                                                phenyl                                                                    581  4-N-benzylamidino-                                                                          n-butyloxycarbonyl                                                                        OMe                                                    phenyl                                                                    582  4-N-methylamidino-                                                                          n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    583  4-N-ethylamidino-                                                                           n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    584  4-N-n-propylamidino-                                                                        n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    585  4-N-n-butylamidino-                                                                         n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    586  4-N-benzylamidino-                                                                          n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    589  4-(acetoxyamidino)-                                                                         n-butyloxycarbonyl                                                                        OMe                                                    phenyl                                                                    590  4-(acetoxyamidino)-                                                                         n-butyloxycarbonyl                                                                        OH                                                     phenyl                                                                    591  4-(acetoxyamidino)-                                                                         isobutyloxycarbonyl                                                                       OMe                                                    phenyl                                                                    592  4-(acetoxyamidino)                                                                          isobutyloxycarbonyl                                                                       OH                                                     phenyl                                                                    593  4-(acetoxyamidino)-                                                                         cyclopropylethoxy-                                                                        OMe                                                    phenyl       carbonyl                                                     594  4-(acetoxyamidino)-                                                                         cyclopropylethoxy-                                                                        OH                                                     phenyl       carbonyl                                                     595  4-(acetoxyamidino)-                                                                         benzyloxycarbonyl                                                                         OMe                                                    phenyl                                                                    596  4-(acetoxyamidino)-                                                                         benzyloxycarbonyl                                                 phenyl                                                                    597  4-(acetoxyamidino)-                                                                         4-methylphenylsulfonyl                                                                    OMe                                                    phenyl                                                                    598  4-(acetoxyamidino)-                                                                         4-methylphenylsulfonyl                                                                    OH                                                     phenyl                                                                    599  4-(acetoxyamidino)-                                                                         3-methylphenylsulfonyl                                                                    OMe                                                    phenyl                                                                    600  4-(acetoxyamidino)-                                                                         3-methylphenylsulfonyl                                                                    OH                                                     phenyl                                                                    601  4-guanidinophenyl                                                                           n-butyloxycarbonyl                                                                        OH                                                602  4-guanidinophenyl                                                                           n-butyloxycarbonyl                                                                        OMe 463                                           603  4-guanidinophenyl                                                                           benzyloxycarbonyl                                                                         OH                                                604  4-guanidinophenyl                                                                           benzyloxycarbonyl                                                                         OMe                                               605  4-guanidinophenyl                                                                           4-methylphenylsulfonyl                                                                    OH  503                                           606  4-guanidinophenyl                                                                           4-methylphenylsulfonyl                                                                    OMe 517                                           607  4-guanidinophenyl                                                                           3-methylphenylsulfonyl                                                                    OH                                                608  4-guanidinophenyl                                                                           3-methylphenylsulfonyl                                                                    OMe                                               609  4-guanidinophenyl                                                                           n-butylsulfonyl                                                                           OH                                                610  4-guanidinophenyl                                                                           n-butylsulfonyl                                                                           OMe                                               613  4-amidino-2-fluoro-                                                                         n-butyloxycarbonyl                                                                        OMe 466                                                phenyl                                                                    614  4-piperidinyl                                                                               n-butyloxycarbonyl                                                                        OMe 412                                           615  4-piperidinylmethyl                                                                         n-butyloxycarbonyl                                                                        OMe 426                                           616  4-piperidinylpropyl                                                                         n-butyloxycarbonyl                                                                        OMe 454                                           617  4-quanidinophenyl                                                                           n-butyloxycarbonyl                                                                        OH  449                                           618  4-amidinophenylmethyl                                                                       benzyloxycarbonyl                                                                         OMe                                               619  4-amidinophenylmethyl                                                                       benzyloxycarbonyl                                                                         OH                                                220  4-amidinophenylmethyl                                                                       n-butyloxycarbonyl                                                                        OMe                                               621  4-amidinophenylmethyl                                                                       n-butyloxycarbonyl                                                                        OH                                                622  4-amidinophenylmethyl                                                                       cyclopropylethoxy                                                                         OMe                                                                 carbonyl                                                     623  4-amidinophenylmethyl                                                                       cyclopropylethoxy                                                                         OH                                                                  carbonyl                                                     624  4-amidinophenylmethyl                                                                       4-methylphenylsulfonyl                                                                    OMe                                               625  4-amidinophenylmethyl                                                                       4-methylphenylsulfonyl                                                                    OH  488                                           626  4-amidinophenylmethyl                                                                       3-methylphenylsulfonyl                                                                    OMe                                               627  4-amidinophenylmethyl                                                                       3-methylphenylsulfonyl                                                                    OH                                                628  4-amidinophenylmethyl                                                                       n-butylsulfonyl                                                                           OMe                                               629  4-amidinophenylmethyl                                                                       n-butylsulfonyl                                                                           OH                                                630  4-amidinophenylmethoxy                                                                      benzyloxycarbonyl                                                                         OMe                                               631  4-amidinophenylmethoxy                                                                      benzyloxycarbonyl                                                                         OH                                                632  4-amidinophenylmethoxy                                                                      n-butyloxycarbonyl                                                                        OMe                                               633  4-amidinophenylmethoxy                                                                      n-butyloxycarbonyl                                                                        OH                                                634  4-amidinophenylmethoxy                                                                      cyclopropylethoxy                                                                         OMe                                                                 carbonyl                                                     635  4-amidinophenylmethoxy                                                                      cyclopropylethoxy                                                                         OH                                                                  carbonyl                                                     636  4-amidinophenylmethoxy                                                                      4-methylphenylsulfonyl                                                                    OMe                                               637  4-amidinophenylmethoxy                                                                      4-methylphenylsulfonyl                                                                    OH                                                638  4-amidinophenylmethoxy                                                                      3-methylphenylsulfonyl                                                                    OMe                                               639  4-amidinophenylmethoxy                                                                      3-methylphenylsulfonyl                                                                    OH                                                640  4-amidinophenylmethoxy                                                                      n-butylsulfonyl                                                                           OMe                                               641  4-amidinophenylmethoxy                                                                      n-butylsulfonyl                                                                           OH                                                642  4-amidinophenyl                                                                             5-chloro-1,3-                                                                             OMe 526                                                             dimethyl-4-pyrazolyl                                         643  4-amidinophenyl                                                                             1-methylimidazol-4-                                                                       OH  478                                                             ylsulfonyl                                                   644  4-amidinophenyl                                                                             3,5-dimethyl-1,3-                                                                         OH  509                                                             thioimidazole-2-                                                               ylsulfonyl                                                   645  N-t-butyloxycarbonyl-4-                                                                     5-(2-pyridinyl)-2-                                                                        OMe 671                                                amidinophenyl                                                                               thienylsulfonyl                                              646  N-t-butyloxycarbonyl-4-                                                                     3,5-dimethyl-1,3                                                                          OMe 623                                                amidinophenyl                                                                               thioimidazole-2-                                                               ylsulfonyl                                                   647  N-t-butyloxycarbonyl-                                                                       3,5-dimethylisoxazol-                                                                     OMe 607                                                4-amidinophenyl                                                                             4-ylsulfonyl                                                      TFA salt, 5(R),N.sup.2 (S)                                                     isomer                                                                    __________________________________________________________________________

                                      TABLE 2B                                     __________________________________________________________________________      ##STR181##                                                                    Example                          MS                                            Number                                                                              R.sup.1 -V                                                                             R.sup.5a                                                                            R.sup.16    Y  (M + H).sup.+                                 __________________________________________________________________________     651  4-amidinophenyl                                                                        methyl                                                                              benzyloxycarbony                                                                           OMe                                                                               496                                           652  4-amidinophenyl                                                                        methyl                                                                              n-butyloxycarbony                                                                          OMe                                              653  4-amidinophenyl                                                                        methyl                                                                              3-methylphenylsulfonyl                                                                     OMe                                              654  4-amidinophenyl                                                                        methyl                                                                              benzyloxycarbonyl                                                                          OH                                               655  4-amidinophenyl                                                                        methyl                                                                              n-butyloxycarbonyl                                                                         OH                                               656  4-amidinophenyl                                                                        methyl                                                                              3-methylphenylsulfonyl                                                                     OH                                               657  4-amidinophenyl                                                                        methyl                                                                              4-methylphenylsulfonyl                                                                     OH                                               658  4-amidinophenyl                                                                        methyl                                                                              4-methylphenylsulfonyl                                                                     OMe                                              659  4-amidinophenyl                                                                        methyl                                                                              n-butylsulfonyl                                                                            OH                                               660  4-amidinophenyl                                                                        methyl                                                                              n-butylsulfonyl                                                                            OMe                                              __________________________________________________________________________

                                      TABLE 2C                                     __________________________________________________________________________      ##STR182##                                                                    Example                         MS                                             Number                                                                              R.sup.1 -V                                                                              R.sup.16   R.sup.17                                                                           Y  (M + H).sup.+                                  __________________________________________________________________________     661  4-amidinophenyl                                                                         benzyloxycarbonyl                                                                         methyl                                                                             OMe                                               662  4-amidinophenyl                                                                         benzyloxycarbonyl                                                                         methyl                                                                             OH                                                663  4-amidinophenyl                                                                         n-butyloxycarbonyl                                                                        methyl                                                                             OMe                                               664  4-amidinophenyl                                                                         n-butyloxycarbonyl                                                                        methyl                                                                             OH                                                665  4-amidinophenyl                                                                         3-methylphenylsulfonyl                                                                    methyl                                                                             OMe                                               666  4-amidinophenyl                                                                         3-methylphenylsulfonyl                                                                    methyl                                                                             OH 502                                            667  4-amidinophenyl                                                                         4-methylphenylsulfonyl                                                                    methyl                                                                             OMe                                               668  4-amidinophenyl                                                                         4-methylphenylsulfonyl                                                                    methyl                                                                             OH                                                669  4-amidinophenyl                                                                         n-butylsulfonyl                                                                           methyl                                                                             OMe                                               670  4-amidinophenyl                                                                         n-butylsulfonyl                                                                           methyl                                                                             OH                                                __________________________________________________________________________

                  TABLE 2D                                                         ______________________________________                                          ##STR183##                                                                    Example                               MS                                       Number R.sup.1 --V  R.sup.16     Y    (M +  H).sup.+                           ______________________________________                                         701    4-amidinophenyl                                                                             benzyloxycarbonyl                                                                           OH                                            702    4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                          OH                                            703    4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                          OH                                            704    4-amidinophenyl                                                                             ethyloxycarbonyl                                                                            OH                                            705    4-amidinophenyl                                                                             methyloxycarbonyl                                                                           OH                                            706    4-amidinophenyl                                                                             phenylethylcarbonyl                                                                         OH                                            707    4-amidinophenyl                                                                             2,2-dimethyl-                                                                               OH                                                                propylcarbonyl                                             708    4-amidinophenyl                                                                             n-pentylcarbonyl                                                                            OH                                            709    4-amidinophenyl                                                                             n-butylcarbonyl                                                                             OH                                            710    4-amidinophenyl                                                                             propionyl    OH                                            711    4-amidinophenyl                                                                             acetyl       OH                                            712    4-amidinophenyl                                                                             methylsulfonyl                                                                              OH                                            713    4-amidinophenyl                                                                             ethylsulfonyl                                                                               OH                                            714    4-amidinophenyl                                                                             n-butylsulfonyl                                                                             OH                                            715    4-amidinophenyl                                                                             phenylsulfonyl                                                                              OH                                            716    4-amidinophenyl                                                                             4-methylphenyl-                                                                             OH                                                                sulfonyl                                                   717    4-amidinophenyl                                                                             benzylsulfonyl                                                                              OH   488                                      718    4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                           OH                                            719    4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                           OH                                            720    4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                           OH                                            721    4-amidinophenyl                                                                             2-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   722    4-amidinophenyl                                                                             3-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   723    4-amidinophenyl                                                                             4-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   724    4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   725    4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   726    4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   727    4-amidinophenyl                                                                             benzyloxycarbonyl                                                                           OMe  480                                      728    4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                          OMe                                           729    4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                          OMe  446                                      730    4-amidinophenyl                                                                             ethyloxycarbonyl                                                                            OMe                                           731    4-amidinophenyl                                                                             methyloxycarbonyl                                                                           OMe                                           732    4-amidinophenyl                                                                             phenylethylcarbonyl                                                                         OMe                                           733    4-amidinophenyl                                                                             2,2-dimethyl-                                                                               OMe                                                               propylcarbonyl                                             734    4-amidinophenyl                                                                             n-pentylcarbonyl                                                                            OMe                                           735    4-amidinophenyl                                                                             n-butylcarbonyl                                                                             OMe                                           736    4-amidinophenyl                                                                             propionyl    OMe                                           737    4-amidinophenyl                                                                             acetyl       OMe                                           738    4-amidinophenyl                                                                             methylsulfonyl                                                                              OMe                                           739    4-amidinophenyl                                                                             ethylsulfonyl                                                                               OMe                                           740    4-amidinophenyl                                                                             n-butylsulfonyl                                                                             OMe                                           741    4-amidinophenyl                                                                             phenylsulfonyl                                                                              OMe                                           742    4-amidinophenyl                                                                             4-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   743    4-amidinophenyl                                                                             benzylsulfonyl                                                                              OMe                                           744    4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                           OMe                                           745    4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                           OMe                                           746    4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                           OMe                                           747    4-amidinophenyl                                                                             2-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   748    4-amidinophenyl                                                                             3-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   749    4-amidinophenyl                                                                             4-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   750    4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   751    4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   752    4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   753    4-piperidinylethyl                                                                          benzylcarbonyl                                                                              OMe                                           754    4-(BOCamidi- benzyloxycarbonyl                                                                           OMe                                                  no)phenyl                                                               755    4-(BOCamidi- n-butyloxycarbonyl                                                                          OMe                                                  no)phenyl                                                               756    4-amidinophenyl                                                                             1-naphthylsulfonyl                                                                          OMe                                           757    4-amidinophenyl                                                                             2-naphthylsulfonyl                                                                          OMe                                           758    4-piperidinylethyl                                                                          n-butyloxycarbonyl                                                                          OMe  440                                      759    4-amidinophenyl                                                                             2-thienylsulfonyl                                                                           OMe                                           760    4-amidinophenyl                                                                             3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   761    4-amidinophenyl                                                                             4-fluorophenyl-                                                                             OMe                                                               sulfonyl                                                   762    4-amidinophenyl                                                                             4-methoxyphenyl-                                                                            OMe                                                               sulfonyl                                                   763    4-amidinophenyl                                                                             n-propylsulfonyl                                                                            OMe                                           764    4-amidinophenyl                                                                             2-phenylethyl-                                                                              OMe                                                               sulfonyl                                                   765    4-amidinophenyl                                                                             4-isopropylphenyl-                                                                          OMe                                                               sulfonyl                                                   766    4-amidinophenyl                                                                             3-phenylpropyl-                                                                             OMe                                                               sulfonyl                                                   767    4-amidinophenyl                                                                             3-pyridylsulfonyl                                                                           OMe                                           768    4-amidinophenyl                                                                             2-pyridylsulfonyl                                                                           OMe                                           769    4-amidinophenyl                                                                             n-butylamino-                                                                               OMe                                                               sulfonyl                                                   770    4-amidinophenyl                                                                             i-butylamino-                                                                               OMe                                                               sulfonyl                                                   771    4-amidinophenyl                                                                             t-butylamino-                                                                               OMe                                                               sulfonyl                                                   772    4-amidinophenyl                                                                             i-propylamino-                                                                              OMe                                                               sulfonyl                                                   773    4-amidinophenyl                                                                             cyclohexylamino-                                                                            OMe                                                               sulfonyl                                                   774    4-amidinophenyl                                                                             phenylamino- OMe                                                               sulfonyl                                                   775    4-amidinophenyl                                                                             benzylamino- OMe                                                               sulfonyl                                                   776    4-amidinophenyl                                                                             dimethylamino-                                                                              OMe                                                               sulfonyl                                                   777    2-fluoro-4-amidino-                                                                         3-methylphenyl-                                                                             OMe                                                  phenyl       sulfonyl                                                   778    5-amidino-2-pyridyl                                                                         n-butyloxycarbonyl                                                                          OMe                                           779    5-amidino-2-pyridyl                                                                         3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   780    6-amidino-3-pyridyl                                                                         n-butyloxycarbonyl                                                                          OMe                                           781    6-amidino-3-pyridyl                                                                         3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   782    4-amidinophenyl                                                                             phenylamino- OMe                                                               carbonyl                                                   783    4-amidinophenyl                                                                             benzylamino- OMe                                                               carbonyl                                                   784    4-amidinophenyl                                                                             n-butylamino-                                                                               OMe                                                               carbonyl                                                   785    4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                          OMe                                           786    4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                          OH                                            787    4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                         OMe                                           788    4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                         OH                                            789    4-amidinophenyl                                                                             2-cyclopropyl-                                                                              OMe                                                               ethoxycarbonyl                                             790    4-amidinophenyl                                                                             2-cyclopropyl-                                                                              OH                                                                ethoxycarbonyl                                             791    4-amidinophenyl                                                                             2-cyclopentyl-                                                                              OMe                                                               ethoxycarbonyl                                             792    4-amidinophenyl                                                                             2-cyclopentyl-                                                                              OH                                                                ethoxycarbonyl                                             793    4-amidinophenyl                                                                             n-propylsulfonyl                                                                            OMe                                           794    4-amidinophenyl                                                                             2-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   795    4-amidinophenyl                                                                             2-benzothienyl-                                                                             OMe                                                               sulfonyl                                                   796    4-amidinophenyl                                                                             2-benzothienyl-                                                                             OMe                                                               sulfonyl                                                   797    4-amidinophenyl                                                                             2,2,5,7,8-penta-                                                                            OH                                                                methyl                                                                         3,4-dihydro-                                                                   2Hbenzo-                                                                       pyran-6-ylsulfonyl                                         798    4-amidinophenyl                                                                             3-methylphenyl-                                                                             OH   486                                                          sulfonyl                                                   ______________________________________                                    

                  TABLE 2E                                                         ______________________________________                                          ##STR184##                                                                    Example                               MS                                       Number R.sup.1 --V  R.sup.16     Y    (M +  H).sup.+                           ______________________________________                                         801    4-amidinophenyl                                                                             benzyloxycarbonyl                                                                           OH                                            802    4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                          OH                                            803    4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                          OH                                            804    4-amidinophenyl                                                                             ethyloxycarbonyl                                                                            OH                                            805    4-amidinophenyl                                                                             methyloxycarbonyl                                                                           OH                                            806    4-amidinophenyl                                                                             phenylethylcarbonyl                                                                         OH                                            807    4-amidinophenyl                                                                             2,2-dimethyl-                                                                               OH                                                                propylcarbonyl                                             808    4-amidinophenyl                                                                             n-pentylcarbonyl                                                                            OH                                            809    4-amidinophenyl                                                                             n-butylcarbonyl                                                                             OH                                            810    4-amidinophenyl                                                                             propionyl    OH                                            811    4-amidinophenyl                                                                             acetyl       OH                                            812    4-amidinophenyl                                                                             methylsulfonyl                                                                              OH                                            813    4-amidinophenyl                                                                             ethylsulfonyl                                                                               OH                                            814    4-amidinophenyl                                                                             n-butylsulfonyl                                                                             OH                                            815    4-amidinophenyl                                                                             phenylsulfonyl                                                                              OH                                            816    4-amidinophenyl                                                                             4-methylphenyl-                                                                             OH   488                                                          sulfonyl                                                   817    4-amidinophenyl                                                                             benzylsulfonyl                                                                              OH                                            818    4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                           OH                                            819    4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                           OH                                            820    4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                           OH                                            821    4-amidinophenyl                                                                             2-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   822    4-amidinophenyl                                                                             3-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   823    4-amidinophenyl                                                                             4-pyridylmethyl-                                                                            OH                                                                carbonyl                                                   824    4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   825    4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   826    4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                           OH                                                                carbonyl                                                   827    4-amidinophenyl                                                                             benzyloxycarbonyl                                                                           OMe                                           828    4-amidinophenyl                                                                             t-butyloxycarbonyl                                                                          OMe                                           829    4-amidinophenyl                                                                             n-butyloxycarbonyl                                                                          OMe  448                                      830    4-amidinophenyl                                                                             ethyloxycarbonyl                                                                            OMe                                           831    4-amidinophenyl                                                                             methyloxycarbonyl                                                                           OMe                                           832    4-amidinophenyl                                                                             phenylethylcarbonyl                                                                         OMe                                           833    4-amidinophenyl                                                                             2,2-dimethyl-                                                                               OMe                                                               propylcarbonyl                                             834    4-amidinophenyl                                                                             n-pentylcarbonyl                                                                            OMe                                           835    4-amidinophenyl                                                                             n-butylcarbonyl                                                                             OMe                                           836    4-amidinophenyl                                                                             propionyl    OMe                                           837    4-amidinophenyl                                                                             acetyl       OMe                                           838    4-amidinophenyl                                                                             methylsulfonyl                                                                              OMe                                           839    4-amidinophenyl                                                                             ethylsulfonyl                                                                               OMe                                           840    4-amidinophenyl                                                                             n-butylsulfonyl                                                                             OMe                                           841    4-amidinophenyl                                                                             phenylsulfonyl                                                                              OMe                                           842    4-amidinophenyl                                                                             4-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   843    4-amidinophenyl                                                                             benzylsulfonyl                                                                              OMe                                           844    4-amidinophenyl                                                                             2-pyridylcarbonyl                                                                           OMe                                           845    4-amidinophenyl                                                                             3-pyridylcarbonyl                                                                           OMe                                           846    4-amidinophenyl                                                                             4-pyridylcarbonyl                                                                           OMe                                           847    4-amidinophenyl                                                                             2-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   848    4-amidinophenyl                                                                             3-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   849    4-amidinophenyl                                                                             4-pyridylmethyl-                                                                            OMe                                                               carbonyl                                                   850    4-amidinophenyl                                                                             2-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   851    4-amidinophenyl                                                                             3-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   852    4-amidinophenyl                                                                             4-pyridylmethoxy-                                                                           OMe                                                               carbonyl                                                   853    4-piperidinylethyl                                                                          benzylcarbonyl                                                                              OMe                                           854    4-(BOCamidi- benzyloxycarbonyl                                                                           OMe                                                  no)phenyl                                                               855    4-(BOCamidi- n-butyloxycarbonyl                                                                          OMe                                                  no)phenyl                                                               856    4-amidinophenyl                                                                             1-naphthylsulfonyl                                                                          OMe                                           857    4-amidinophenyl                                                                             2-naphthylsulfonyl                                                                          OMe                                           858    4-piperidinylethyl                                                                          n-butyloxycarbonyl                                                                          OMe                                           859    4-amidinophenyl                                                                             2-thienylsulfonyl                                                                           OMe                                           860    4-amidinophenyl                                                                             3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   861    4-amidinophenyl                                                                             4-fluorophenyl-                                                                             OMe                                                               sulfonyl                                                   862    4-amidinophenyl                                                                             4-methoxyphenyl-                                                                            OMe                                                               sulfonyl                                                   863    4-amidinophenyl                                                                             n-propylsulfonyl                                                                            OMe                                           864    4-amidinophenyl                                                                             2-phenylethyl-                                                                              OMe                                                               sulfonyl                                                   865    4-amidinophenyl                                                                             4-isopropylphenyl-                                                                          OMe                                                               sulfonyl                                                   866    4-amidinophenyl                                                                             3-phenylpropyl-                                                                             OMe                                                               sulfonyl                                                   867    4-amidinophenyl                                                                             3-pyridylsulfonyl                                                                           OMe                                           868    4-amidinophenyl                                                                             2-pyridylsulfonyl                                                                           OMe                                           869    4-amidinophenyl                                                                             n-butylamino-                                                                               OMe                                                               sulfonyl                                                   870    4-amidinophenyl                                                                             i-butylamino-                                                                               OMe                                                               sulfonyl                                                   871    4-amidinophenyl                                                                             t-butylamino-                                                                               OMe                                                               sulfonyl                                                   872    4-amidinophenyl                                                                             i-propylamino-                                                                              OMe                                                               sulfonyl                                                   873    4-amidinophenyl                                                                             cyclohexylamino-                                                                            OMe                                                               sulfonyl                                                   874    4-amidinophenyl                                                                             phenylamino- OMe                                                               sulfonyl                                                   875    4-amidinophenyl                                                                             benzylamino- OMe                                                               sulfonyl                                                   876    4-amidinophenyl                                                                             dimethylamino-                                                                              OMe                                                               sulfonyl                                                   877    2-fluoro-4-amidino-                                                                         3-methylphenyl-                                                                             OMe                                                  phenyl       sulfonyl                                                   878    5-amidino-2-pyridyl                                                                         n-butyloxycarbonyl                                                                          OMe                                           879    5-amidino-2-pyridyl                                                                         3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   880    6-amidino-3-pyridyl                                                                         n-butyloxycarbonyl                                                                          OMe                                           881    6-amidino-3-pyridyl                                                                         3-methylphenyl-                                                                             OMe                                                               sulfonyl                                                   882    4-amidinophenyl                                                                             phenylamino- OMe                                                               carbonyl                                                   883    4-amidinophenyl                                                                             benzylamino- OMe                                                               carbonyl                                                   884    4-amidinophenyl                                                                             n-butylamino-                                                                               OMe                                                               carbonyl                                                   885    4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                          OMe                                           886    4-amidinophenyl                                                                             n-hexyloxycarbonyl                                                                          OH                                            887    4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                         OMe                                           888    4-amidinophenyl                                                                             isobutyloxycarbonyl                                                                         OH                                            889    4-amidinophenyl                                                                             2-cyclopropyl-                                                                              OMe                                                               ethoxycarbonyl                                             890    4-amidinophenyl                                                                             2-cyclopropyl-                                                                              OH                                                                ethoxycarbonyl                                             891    4-amidinophenyl                                                                             2-cyclopentyl-                                                                              OMe                                                               ethoxycarbonyl                                             892    4-amidinophenyl                                                                             2-cyclopentyl-                                                                              OH                                                                ethoxycarbonyl                                             893    4-amidinophenyl                                                                             n-propylsulfonyl                                                                            OMe                                           894    4-amidinophenyl                                                                             2-methylphenyl                                                                              OMe                                                               sulfonyl                                                   895    4-amidinophenyl                                                                             2-benzothienyl-                                                                             OMe                                                               sulfonyl                                                   896    4-amidinophenyl                                                                             2-benzothienyl                                                                              OMe                                                               sulfonyl                                                   897    4-amidinophenyl                                                                             2,2,5,7,8-penta-                                                                            OH                                                                methyl                                                                         3,4-dihydro-                                                                   2Hbenzo-                                                                       pyran-6-ylsulfonyl                                         ______________________________________                                    

                                      TABLE 3                                      __________________________________________________________________________                                                        (VII)                        ##STR185##                                                                    Ex.                                              MS                            No.                                                                               R.sup.2                                                                           R.sup.1 --V    --F--E<                                                                               p n'                                                                               Y                (M +  H).sup.+                __________________________________________________________________________     171                                                                               H                                                                                  ##STR186##    --C(═O)--N<                                                                       1 1 OH                                             172                                                                               H                                                                                  ##STR187##    --C(═O)--N<                                                                       1 2 OH                                             173                                                                               H                                                                                  ##STR188##    --C(H.sub.2)--N<                                                                      1 1 OH                                             174                                                                               H                                                                                  ##STR189##    --C(H.sub.2)--N<                                                                      1 2 OH                                             175                                                                               H                                                                                  ##STR190##    --C(H)═C<                                                                         1 1 OH                                             176                                                                               H                                                                                  ##STR191##    --C(H)═C<                                                                         1 2 OH                                             177                                                                               H                                                                                  ##STR192##    --C(═O)--N<                                                                       2 1 OH                                             178                                                                               H                                                                                  ##STR193##    --C(═O)--N<                                                                       2 2 OH                                             179                                                                               H                                                                                  ##STR194##    --C(H.sub.2)--N<                                                                      2 1 OH                                             180                                                                               H                                                                                  ##STR195##    --C(H.sub.2)--N<                                                                      2 2 OH                                             181                                                                               H                                                                                  ##STR196##    --C(H)═C<                                                                         2 1 OH                                             182                                                                               H                                                                                  ##STR197##    --C(H)═C<                                                                         2 2 OH                                             183                                                                               H                                                                                  ##STR198##    --C(═O)--N<                                                                       3 1 OH                                             184                                                                               H                                                                                  ##STR199##    --C(═O)--N<                                                                       3 2 OH                                             185                                                                               H                                                                                  ##STR200##    --C(H.sub.2)--N<                                                                      3 1 OH                                             186                                                                               H                                                                                  ##STR201##    --C(H.sub.2)--N<                                                                      3 2 OH                                             187                                                                               H                                                                                  ##STR202##    --C(H)═C<                                                                         3 1 OH                                             188                                                                               H                                                                                  ##STR203##    --C(H)═C<                                                                         3 2 OH                                             189                                                                               H                                                                                  ##STR204##    --C(═O)--N<                                                                       1 1 OH               338                           190                                                                               H                                                                                  ##STR205##    --C(═O)--N<                                                                       1 2 OH               352                           191                                                                               H                                                                                  ##STR206##    --C(H.sub.2)--N<                                                                      1 1 OH                                             192                                                                               H                                                                                  ##STR207##    --C(H.sub.2)--N<                                                                      1 2 OH                                             193                                                                               H                                                                                  ##STR208##    --C(H)═C<                                                                         1 1 OH                                             194                                                                               H                                                                                  ##STR209##    --C(H)═C<                                                                         1 2 OH                                             195                                                                               H                                                                                  ##STR210##    --C(═O)--N<                                                                       2 1 OH                                             196                                                                               H                                                                                  ##STR211##    --C(═O)--N<                                                                       2 2 OH                                             197                                                                               H                                                                                  ##STR212##    --C(H.sub.2)--N<                                                                      2 1 OH                                             198                                                                               H                                                                                  ##STR213##    --C(H.sub.2)--N<                                                                      2 2 OH                                             199                                                                               H                                                                                  ##STR214##    --C(H)═C<                                                                         2 1 OH                                             200                                                                               H                                                                                  ##STR215##    --C(H)═C<                                                                         2 2 OH                                             201                                                                               H                                                                                  ##STR216##    --C(═O)--N<                                                                       3 1 OH                                             202                                                                               H                                                                                  ##STR217##    --C(═O)--N<                                                                       3 2 OH                                             203                                                                               H                                                                                  ##STR218##    --C(H.sub.2)--N<                                                                      3 1 OH                                             204                                                                               H                                                                                  ##STR219##    --C(H.sub.2)--N<                                                                      3 2 OH                                             205                                                                               H                                                                                  ##STR220##    --C(H)═C<                                                                         3 1 OH                                             206                                                                               H                                                                                  ##STR221##    --C(H)═C<                                                                         3 2 OH                                             207                                                                               Boc                                                                                ##STR222##    --C(═O)--N<                                                                       1 1 OH                                             208                                                                               Cbz                                                                                ##STR223##    --C(═O)--N<                                                                       1 1 OH                                             209                                                                               H                                                                                  ##STR224##    --C(═O)--N<                                                                       1 1                                                                                 ##STR225##                                    210                                                                               H                                                                                  ##STR226##    --C(═O)--N<                                                                       1 1                                                                                 ##STR227##                                    211                                                                               H                                                                                  ##STR228##    --C(═O)--N<                                                                       1 1                                                                                 ##STR229##                                    212                                                                               H                                                                                  ##STR230##    --C(═O)--N<                                                                       1 1                                                                                 ##STR231##                                    213                                                                               H                                                                                  ##STR232##    --C(═O)--N<                                                                       1 1                                                                                 ##STR233##                                    214                                                                               H                                                                                  ##STR234##    --C(═O)--N<                                                                       1 1 OEt                                            215                                                                               H                                                                                  ##STR235##    --C(═O)--N<                                                                       1 2 OEt                                            216                                                                               H                                                                                  ##STR236##    --C(H.sub.2)--N<                                                                      1 1 OEt                                            217                                                                               H                                                                                  ##STR237##    --C(H.sub.2)--N<                                                                      1 2 OEt                                            218                                                                               H                                                                                  ##STR238##    --C(H)═C<                                                                         1 1 OEt                                            219                                                                               H                                                                                  ##STR239##    --C(H)═C<                                                                         1 2 OEt                                            220                                                                               H                                                                                  ##STR240##    --C(═O)--N<                                                                       2 1 OEt                                            221                                                                               H                                                                                  ##STR241##    --C(═O)--N<                                                                       2 2 OEt                                            222                                                                               H                                                                                  ##STR242##    --C(H.sub.2)--N<                                                                      2 1 OEt                                            223                                                                               H                                                                                  ##STR243##    --C(H.sub.2)--N<                                                                      2 2 OEt                                            224                                                                               H                                                                                  ##STR244##    --C(H)═C<                                                                         2 1 OEt                                            225                                                                               H                                                                                  ##STR245##    --C(H)═C<                                                                         2 2 OEt                                            226                                                                               H                                                                                  ##STR246##    --C(═O)--N<                                                                       3 1 OEt                                            227                                                                               H                                                                                  ##STR247##    --C(═O)--N<                                                                       3 2 OEt                                            228                                                                               H                                                                                  ##STR248##    --C(H.sub.2)--N<                                                                      3 1 OEt                                            229                                                                               H                                                                                  ##STR249##    --C(H.sub.2)--N<                                                                      3 2 OEt                                            230                                                                               H                                                                                  ##STR250##    --C(H)═C<                                                                         3 1 OEt                                            231                                                                               H                                                                                  ##STR251##    --C(H)═C<                                                                         3 2 OEt                                            232                                                                               H                                                                                  ##STR252##    --C(═O)--N<                                                                       1 1 OEt                                            233                                                                               H                                                                                  ##STR253##    --C(═O)--N<                                                                       1 2 OEt                                            234                                                                               H                                                                                  ##STR254##    --C(H.sub.2)--N<                                                                      1 1 OEt                                            235                                                                               H                                                                                  ##STR255##    --C(H.sub.2)--N<                                                                      1 2 OEt                                            236                                                                               H                                                                                  ##STR256##    --C(H)═C<                                                                         1 1 OEt                                            237                                                                               H                                                                                  ##STR257##    --C(H)═C<                                                                         1 2 OEt                                            238                                                                               H                                                                                  ##STR258##    --C(═O)--N<                                                                       2 1 OEt                                            239                                                                               H                                                                                  ##STR259##    --C(═O)--N<                                                                       2 2 OEt                                            240                                                                               H                                                                                  ##STR260##    --C(H.sub.2)--N<                                                                      2 1 OEt                                            241                                                                               H                                                                                  ##STR261##    --C(H.sub.2)--N<                                                                      2 2 OEt                                            242                                                                               H                                                                                  ##STR262##    --C(H)═C<                                                                         2 1 OEt                                            243                                                                               H                                                                                  ##STR263##    --C(H)═C<                                                                         2 2 OEt                                            244                                                                               H                                                                                  ##STR264##    --C(═O)--N<                                                                       3 1 OEt                                            245                                                                               H                                                                                  ##STR265##    --C(═O)--N<                                                                       3 2 OEt                                            246                                                                               H                                                                                  ##STR266##    --C(H.sub.2)--N<                                                                      3 1 OEt                                            247                                                                               H                                                                                  ##STR267##    --C(H.sub.2)--N<                                                                      3 2 OEt                                            248                                                                               H                                                                                  ##STR268##    --C(H)═C<                                                                         3 1 OEt                                            249                                                                               H                                                                                  ##STR269##    --C(H)═C<                                                                         3 2 OEt                                            250                                                                               Boc                                                                                ##STR270##    --C(═O)--N<                                                                       1 1 OEt                                            251                                                                               Cbz                                                                                ##STR271##    --C(═O)--N<                                                                       1 1 OEt                                            373                                                                               H                                                                                  ##STR272##    --C(═O)--N<                                                                       1 2 OH               366                           __________________________________________________________________________

                                      TABLE 4                                      __________________________________________________________________________                                         (VIII)                                      ##STR273##                                                                    Example                                                                        Number                                                                              R.sup.2                                                                           R.sup.1a    Z.sup.1                                                                            Y                                                      __________________________________________________________________________     252  H                                                                                  ##STR274## CH.sub.2                                                                           OH                                                     253  H  --NHCH.sub.2).sub.2 --                                                                     CH.sub.2                                                                           OH                                                     254  H  --NHCH.sub.2).sub.3 --                                                                     CH.sub.2                                                                           OH                                                     255  H                                                                                  ##STR275## O   OH                                                     256  H  --NHCH.sub.2).sub.2 --                                                                     O   OH                                                     257  H  --NHCH.sub.2).sub.3 --                                                                     O   OH                                                     258  Boc                                                                                ##STR276## CH.sub.2                                                                           OH                                                     259  Cbz                                                                                ##STR277## CH.sub.2                                                                           OH                                                     260  H                                                                                  ##STR278## CH.sub.2                                                                            ##STR279##                                            261  H                                                                                  ##STR280## CH.sub.2                                                                            ##STR281##                                            262  H                                                                                  ##STR282## CH.sub.2                                                                            ##STR283##                                            263  H                                                                                  ##STR284## CH.sub.2                                                                            ##STR285##                                            264  H                                                                                  ##STR286## CH.sub.2                                                                            ##STR287##                                            265  H                                                                                  ##STR288## CH.sub.2                                                                           OEt                                                    266  H                                                                                  ##STR289## CH.sub.2                                                                           OEt                                                    267  H                                                                                  ##STR290## CH.sub.2                                                                           OEt                                                    268  H  --NH(CH.sub.2).sub.2 --                                                                    CH.sub.2                                                                           OEt                                                    269  H  --NH(CH.sub.2).sub.3 --                                                                    CH.sub.2                                                                           OEt                                                    270  H                                                                                  ##STR291## O   OEt                                                    271  H  --NH(CH.sub.2).sub.2 --                                                                    O   OEt                                                    272  H  --NH(CH.sub.2).sub.3 --                                                                    O   OEt                                                    273  Boc                                                                                ##STR292## CH.sub.2                                                                           OEt                                                    274  Cbz                                                                                ##STR293## CH.sub.2                                                                           OEt                                                    __________________________________________________________________________

                  TABLE 5                                                          ______________________________________                                          ##STR294##                                                                    Example                             MS (ESI)                                   Number R                     Y      (M +  H).sup.+                             ______________________________________                                         375                                                                                    ##STR295##           OH     373                                        376                                                                                    ##STR296##           OH                                                377                                                                                    ##STR297##           OH     387                                        378                                                                                    ##STR298##           OH                                                379                                                                                    ##STR299##           OH                                                380                                                                                    ##STR300##           OH                                                381                                                                                    ##STR301##           OH                                                382                                                                                    ##STR302##           OH                                                383                                                                                    ##STR303##           OH     415                                        384                                                                                    ##STR304##           OH                                                385                                                                                    ##STR305##           OH                                                386                                                                                    ##STR306##           OH                                                387                                                                                    ##STR307##           OH                                                388                                                                                    ##STR308##           OH                                                389                                                                                    ##STR309##           OH                                                394                                                                                    ##STR310##           OMe    387                                        395                                                                                    ##STR311##           OMe                                               396                                                                                    ##STR312##           OMe                                               397                                                                                    ##STR313##           OMe                                               398                                                                                    ##STR314##           OMe                                               399                                                                                    ##STR315##           OMe                                               400                                                                                    ##STR316##           OMe    402                                        401                                                                                    ##STR317##           OMe                                               402                                                                                    ##STR318##           OMe                                               403                                                                                    ##STR319##           OMe                                               404                                                                                    ##STR320##           OMe                                               405                                                                                    ##STR321##           OMe                                               406                                                                                    ##STR322##           OMe                                               407                                                                                    ##STR323##           OMe                                               408                                                                                    ##STR324##           OMe                                               413                                                                                    ##STR325##           OEt    401                                        414                                                                                    ##STR326##           OEt                                               415                                                                                    ##STR327##           OEt    415                                        416                                                                                    ##STR328##           OEt                                               417                                                                                    ##STR329##           OEt                                               418                                                                                    ##STR330##           OEt                                               419                                                                                    ##STR331##           OEt                                               420                                                                                    ##STR332##           OEt                                               421                                                                                    ##STR333##           OEt                                               422                                                                                    ##STR334##           OEt                                               423                                                                                    ##STR335##           OEt                                               424                                                                                    ##STR336##           OEt                                               425                                                                                    ##STR337##           OEt                                               426                                                                                    ##STR338##           OEt                                               427                                                                                    ##STR339##           OEt                                               432    --NHC(CH.sub.3).sub.2 --                                                                             OEt.                                                     CH.sub.2 C(═O)Y                                                     433    --N(CH.sub.2 C.sub.6 H.sub.5)--                                                                      OEt                                                      (CH.sub.2).sub.2 C(═O)Y                                             436                                                                                    ##STR340##           OEt    387                                        437                                                                                    ##STR341##           OEt    387                                        438                                                                                    ##STR342##           OMe    387                                        899                                                                                    ##STR343##           OMe                                               900                                                                                    ##STR344##           OH                                                ______________________________________                                    

                                      TABLE 6                                      __________________________________________________________________________      ##STR345##                                                                    Ex.                                    (M +  H).sup.+                          No.                                                                               R.sup.2                                                                              R.sup.3                                                                            R.sup.4a       X     Y    ESI                                     __________________________________________________________________________     950                                                                               H     H   3-methyl-      2-fluoro-                                                                            OCH.sub.3                                                                           521                                                  phenyl-        phen-1,4-                                                       sulfonyl       diyl                                               951                                                                               H     H   3-methyl-      2-fluoro-                                                                            OH   507                                                  phenyl-        phen-1,4-                                                       sulfonyl       diyl                                               952                                                                                ##STR346##                                                                          H   3-methyl-  phenyl-  sulfonyl                                      phen-1,4-  diyl                                                                   OCH.sub.3                                                                            545                                                                   953                                                                                ##STR347##                                                                          H   3-methyl-  phenyl-  sulfonyl                                      phen-1,4-  diyl                                                                   OH    532                                                                   954                                                                               H     H   n-butoxy-                                                         phen-1,4-                                                                         OH    435                                                                                carbonyl       diyl                                               955                                                                               H     H   3-methyl-                                                         phen-1,4-                                                                         OCH.sub.3                                                                            503                                                                                phenyl-        diyl                                                            sulfonyl                                                          956                                                                               H     H   3-methyl-                                                         phen-1,4-                                                                         OH    489                                                                                phenyl-        diyl                                                            sulfonyl                                                          957                                                                               H     H                                                                                   ##STR348##                                                       phen-1,4-  diyl                                                                   OH    527                                                                   958                                                                               H     H   4-CF.sub.3 -                                                      phen-1,4-                                                                         OH    543                                                                                phenyl-        diyl                                                            sulfonyl                                                          959                                                                               H     H                                                                                   ##STR349##                                                       phen-1,4-  diyl                                                                   OH                                                                          960                                                                               o-CH.sub.3 O-                                                                        H   3-methyl-                                                         phen-1,4-                                                                         OH                                                                             benzyl    phenyl-        diyl                                                            sulfonyl                                                          961                                                                               o-CH.sub.3 O-  benzyl                                                                H                                                                                   ##STR350##                                                       phen-1,4-  diyl                                                                   OH                                                                          962                                                                               o-CH.sub.3 O-  benzyl                                                                CH.sub.3                                                                            ##STR351##                                                       phen-1,4-  diyl                                                                   OH                                                                          963                                                                               o-CH.sub.3 O-                                                                        CH.sub.3                                                                           3-methyl-                                                         phen-1,4-                                                                         OH                                                                             benzyl    phenyl-        diyl                                                            sulfonyl                                                          964                                                                               H     H   2-fluoro-                                                         phen-1,4-                                                                         OH    493                                                                                phenyl-        diyl                                                            sulfonyl                                                          965                                                                               H     H   4-CF.sub.3 -                                                      phen-1,4-                                                                         OH    543                                                                                phenyl-        diyl                                                            sulfonyl                                                          966                                                                               H     H   4-Cl-                                                             phen-1,4-                                                                         OH    509                                                                                phenyl-        diyl                                                            sulfonyl                                                          967                                                                               H     H                                                                                   ##STR352##                                                       phen-1,4-  diyl                                                                   OH    525                                                                   968                                                                               3-(CF.sub.3)-  benzyl                                                                H                                                                                   ##STR353##                                                       phen-1,4-  diyl                                                                   OH                                                                          969                                                                               3-(CF.sub.3)-  benzyl                                                                H                                                                                   ##STR354##                                                       phen-1,4-  diyl                                                                   OH                                                                          970                                                                               3-(CF.sub.3)-                                                                        CH.sub.3                                                                           3-methyl                                                          phen-1,4-                                                                         OH                                                                             benzyl    phenyl-        diyl                                                            sulfonyl                                                          971                                                                               3-(CF.sub.3)-  benzyl                                                                CH.sub.3                                                                            ##STR355##                                                       phen-1,4-  diyl                                                                   OH                                                                          972                                                                               nBu-  H   3-methyl-                                                         phen-1,4-                                                                         OH                                                                                       phenyl-        diyl                                                            sulfonyl                                                          973                                                                               nBu-  H                                                                                   ##STR356##                                                       phen-1,4-  diyl                                                                   OH                                                                          974                                                                               nBu-  CH.sub.3                                                                           3-methyl-                                                         phen-1,4-                                                                         OH                                                                                       phenyl-        diyl                                                            sulfonyl                                                          975                                                                               nBu-  CH.sub.3                                                                            ##STR357##                                                       phen-1,4-  diyl                                                                   OH                                                                          976                                                                               CH.sub.3                                                                             CH.sub.3                                                                            ##STR358##                                                       phen-1,4-  diyl                                                                   OH                                                                          977                                                                               CH.sub.3                                                                             CH.sub.3                                                                           3-methyl                                                          phen-1,4-                                                                         OH                                                                                       phenyl-        diyl                                                            sulfonyl                                                          978                                                                               H     H   3-methyl-      5-    OMe  490                                                  phenyl-        carboxamido                                                     sulfonyl       pyrid-2-yl                                         979                                                                               H     H   4-ethyl-                                                          phen-1,4-                                                                         OH    503                                                                                phenyl-        diyl                                                            sulfonyl                                                          __________________________________________________________________________

                  TABLE 7                                                          ______________________________________                                          ##STR359##                                                                                                            MS                                     Ex                                      (M +                                   No.   R.sup.1 -V     R.sup.16      Y    H).sup.+                               ______________________________________                                         980   4-amidinophenyl                                                                               H             OH                                          981   4-amidinophenyl                                                                               benzyloxycarbonyl                                                                            OH                                          982   4-amidinophenyl                                                                               t-butyloxycarbonyl                                                                           OH                                          983   4-amidinophenyl                                                                               n-butyloxycarbonyl                                                                           OH                                          984   4-amidinophenyl                                                                               ethyloxycarbonyl                                                                             OH                                          985   4-amidinophenyl                                                                               methyloxycarbonyl                                                                            OH                                          986   4-amidinophenyl                                                                               phenylethylcarbonyl                                                                          OH                                          987   4-amidinophenyl                                                                               2,2-dimethyl- OH                                                               propylcarbonyl                                            988   4-amidinophenyl                                                                               n-pentylcarbonyl                                                                             OH                                          989   4-amidinophenyl                                                                               n-butylcarbonyl                                                                              OH                                          990   4-amidinophenyl                                                                               propionyl     OH                                          991   4-amidinophenyl                                                                               acetyl        OH                                          992   4-amidinophenyl                                                                               methylsulfonyl                                                                               OH                                          993   4-amidinophenyl                                                                               ethylsulfonyl OH                                          994   4-amidinophenyl                                                                               n-butylsulfonyl                                                                              OH                                          995   4-amidinophenyl                                                                               phenylsulfonyl                                                                               OH                                          996   4-amidinophenyl                                                                               4-methylphenyl-                                                                              OH   474                                                         sulfonyl                                                  997   4-amidinophenyl                                                                               benzylsulfonyl                                                                               OH                                          998   4-amidinophenyl                                                                               2-pyridylcarbonyl                                                                            OH                                          999   4-amidinophenyl                                                                               3-pyridylcarbonyl                                                                            OH                                          1000  4-amidinophenyl                                                                               4-pyridylcarbonyl                                                                            OH                                          1001  4-amidinophenyl                                                                               2-pyridylmethyl-                                                                             OH                                                               carbonyl                                                  1002  4-amidinophenyl                                                                               3-pyridylmethyl-                                                                             OH                                                               carbonyl                                                  1003  4-amidinophenyl                                                                               4-pyridylmethyl-                                                                             OH                                                               carbonyl                                                  1004  4-amidinophenyl                                                                               2-pyridylmethoxy-                                                                            OH                                                               carbonyl                                                  1005  4-amidinophenyl                                                                               3-pyridylmethoxy-                                                                            OH                                                               carbonyl                                                  1006  4-amidinophenyl                                                                               4-pyridylmethoxy-                                                                            OH                                                               carbonyl                                                  1007  4-amidinophenyl                                                                               H             OMe                                         1008  4-amidinophenyl                                                                               benzyloxycarbonyl                                                                            OMe                                         1009  4-amidinophenyl                                                                               t-butyloxycarbonyl                                                                           OMe                                         1010  4-amidinophenyl                                                                               n-butyloxycarbonyl                                                                           OMe                                         1011  4-amidinophenyl                                                                               ethyloxycarbonyl                                                                             OMe                                         1012  4-amidinophenyl                                                                               methyloxycarbonyl                                                                            OMe                                         1013  4-amidinophenyl                                                                               phenylethylcarbonyl                                                                          OMe                                         1014  4-amidinophenyl                                                                               2,2-dimethyl- OMe                                                              propylcarbonyl                                            1015  4-amidinophenyl                                                                               n-pentylcarbonyl                                                                             OMe                                         1016  4-amidinophenyl                                                                               n-butylcarbonyl                                                                              OMe                                         1017  4-amidinophenyl                                                                               propionyl     OMe                                         1018  4-amidinophenyl                                                                               acetyl        OMe                                         1019  4-amidinophenyl                                                                               methylsulfonyl                                                                               OMe                                         1020  4-amidinophenyl                                                                               ethylsulfonyl OMe                                         1021  4-amidinophenyl                                                                               n-butylsulfonyl                                                                              OMe                                         1022  4-amidinophenyl                                                                               phenylsulfonyl                                                                               OMe                                         1023  4-amidinophenyl                                                                               4-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1024  4-amidinophenyl                                                                               benzylfulfonyl                                                                               OMe                                         1025  4-amidinophenyl                                                                               2-pyridylcarbonyl                                                                            OMe                                         1026  4-amidinophenyl                                                                               3-pyridylcarbonyl                                                                            OMe                                         1027  4-amidinophenyl                                                                               4-pyridylcarbonyl                                                                            OMe                                         1029  4-amidinophenyl                                                                               2-pyridylmethyl-                                                                             OMe                                                              carbonyl                                                  1030  4-amidinophenyl                                                                               3-pyridylmethyl-                                                                             OMe                                                              carbonyl                                                  1031  4-amidinophenyl                                                                               4-pyridylmethyl-                                                                             OMe                                                              carbonyl                                                  1032  4-amidinophenyl                                                                               2-pyridylmethoxy-                                                                            OMe                                                              carbonyl                                                  1033  4-amidinophenyl                                                                               3-pyridylmethoxy-                                                                            OMe                                                              carbonyl                                                  1034  4-amidinophenyl                                                                               4-pyridylmethoxy-                                                                            OMe                                                              carbonyl                                                  1035  4-piperidinylethyl                                                                            benzylcarbonyl                                                                               OMe                                         1036  4-(BOCamidino)phenyl                                                                          benzyloxycarbonyl                                                                            OMe                                         1037  4-(BOCamidino)phenyl                                                                          n-butyloxycarbonyl                                                                           OMe                                         1038  4-amidinophenyl                                                                               1-naphthylsulfonyl                                                                           OMe                                         1039  4-amidinophenyl                                                                               2-naphthylsulfonyl                                                                           OMe                                         1040  4-amidinophenyl                                                                               styrylsulfonyl                                                                               OMe                                         1041  4-piperidinylethyl                                                                            n-butyloxycarbonyl                                                                           OMe                                         1042  4-amidinophenyl                                                                               4-butyloxyphenyl-                                                                            OMe                                                              sulfonyl                                                  1043  4-amidinophenyl                                                                               2-thienylsulfonyl                                                                            OMe                                         1044  4-amidinophenyl                                                                               3-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1045  4-amidinophenyl                                                                               4-iodophenyl  OMe                                         1046  4-amidinophenyl                                                                               3-trifluoromethyl-                                                                           OMe                                                              phenylsulfonyl                                            1047  4-amidinophenyl                                                                               3-chlorophenyl-                                                                              OMe                                                              sulfonyl                                                  1048  4-amidinophenyl                                                                               2-methoxycarbonyl-                                                                           OMe                                                              phenylsulfonyl                                            1050  4-amidinophenyl                                                                               2,4,6-trimethyl-                                                                             OMe                                                              phenylsulfonyl                                            1051  4-amidinophenyl                                                                               2-chlorophenyl-                                                                              OMe                                                              sulfonyl                                                  1052  4-amidinophenyl                                                                               2-trifluoromethyl-                                                                           OMe                                                              phenylsulfonyl                                            1053  4-amidinophenyl                                                                               4-trifluoromethyl-                                                                           OMe                                                              phenylsulfonyl                                            1054  4-amidinophenyl                                                                               2-fluorophenyl-                                                                              OMe                                                              sulfonyl                                                  1055  4-amidinophenyl                                                                               4-fluorophenyl-                                                                              OMe                                                              sulfonyl                                                  1056  4-amidinophenyl                                                                               4-methoxyphenyl-                                                                             OMe                                                              sulfonyl                                                  1057  4-amidinophenyl                                                                               2,3,4,5,6-tetramethyl-                                                                       OMe                                                              phenylsulfonyl                                            1058  4-amidinophenyl                                                                               4-cyanophenyl-                                                                               OMe                                                              sulfonyl                                                  1059  4-amidinophenyl                                                                               4-chlorophenyl-                                                                              OMe                                                              sulfonyl                                                  1060  4-amidinophenyl                                                                               4-ethylphenyl-                                                                               OMe                                                              sulfonyl                                                  1061  4-amidinophenyl                                                                               4-propylphenyl-                                                                              OMe                                                              sulfonyl                                                  1062  4-amidinophenyl                                                                               n-propylsulfonyl                                                                             OMe                                         1063  4-amidinophenyl                                                                               2-phenylethyl-                                                                               OMe                                                              sulfonyl                                                  1064  4-amidinophenyl                                                                               4-isopropylphenyl-                                                                           OMe                                                              sulfonyl                                                  1065  4-amidinophenyl                                                                               3-phenylpropyl-                                                                              OMe                                                              sulfonyl                                                  1066  4-amidinophenyl                                                                               3-pyridylsulfonyl                                                                            OMe                                         1068  4-amidinophenyl                                                                               2-pyridylsulfonyl                                                                            OMe                                         1069  4-amidinophenyl                                                                               2,2-diphenyl-1-                                                                              OMe                                                              ethenylsulfonyl                                           1070  4-amidinophenyl                                                                               2-pyrimidinyl-                                                                               OMe                                                              sulfonyl                                                  1071  4-amidinophenyl                                                                               4-methyl-2-   OMe                                                              pyrimidinylsulfonyl                                       1072  4-amidinophenyl                                                                               4,6-dimethyl-2-                                                                              OMe                                                              pyrimidinylsulfonyl                                       1073  4-amidinophenyl                                                                               1,2,4-triazol-3-                                                                             OMe                                                              ylsulfonyl                                                1074  4-amidinophenyl                                                                               1-methyl-1,3,4-                                                                              OMe                                                              trizol-5-ylsulfonyl                                       1075  4-amidinophenyl                                                                               3,5-dimethyl-4-                                                                              OMe                                                              pyrazolylsulfonyl                                         1076  4-amidinophenyl                                                                               1-phenyl-4-   OMe                                                              pyrazolylsulfonyl                                         1077  4-amidinophenyl                                                                               n-butylaminosulfonyl                                                                         OMe                                         1078  4-amidinophenyl                                                                               i-butylaminosulfonyl                                                                         OMe                                         1079  4-amidinophenyl                                                                               t-butylaminosulfonyl                                                                         OMe                                         1080  4-amidinophenyl                                                                               i-propylamino-                                                                               OMe                                                              sulfonyl                                                  1081  4-amidinophenyl                                                                               cyclohexylamino-                                                                             OMe                                                              sulfonyl                                                  1082  4-amidinophenyl                                                                               phenylaminosulfonyl                                                                          OMe                                         1083  4-amidinophenyl                                                                               benzylaminosulfonyl                                                                          OMe                                         1084  4-amidinophenyl                                                                               dimethylamino-                                                                               OMe                                                              sulfonyl                                                  1085  4-amidino-2-fluoro-                                                                           3-methylphenyl-                                                                              OMe                                               phenyl         sulfonyl                                                  1086  2-amidino-5-pyridyl                                                                           n-butyloxycarbonyl                                                                           OMe                                         1088  2-amidino-5-pyridyl                                                                           3-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1089  3-amidino-6-pyridyl                                                                           n-butyloxycarbonyl                                                                           OMe                                         1090  3-amidino-6-pyridyl                                                                           3-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1091  4-amidinophenyl                                                                               phenylaminocarbonyl                                                                          OMe                                         1092  4-amidinophenyl                                                                               4-fluorophenylamino-                                                                         OMe                                                              carbonyl                                                  1093  4-amidinophenyl                                                                               1-naphthylamino-                                                                             OMe                                                              carbonyl                                                  1094  4-amidinophenyl                                                                               benzylaminocarbonyl                                                                          OMe                                         1095  4-amidinophenyl                                                                               n-butylaminocarbonyl                                                                         OMe                                         1096  4-amidinophenyl                                                                               4-ethylphenyl-                                                                               OMe                                                              carbonyl                                                  1097  4-amidinophenyl                                                                               biphenylcarbonyl                                                                             OMe                                         1098  4-amidinophenyl                                                                               2-naphthylcarbonyl                                                                           OMe                                         1099  4-amidinophenyl                                                                               (2-chlorophenyl)                                                                             OMe                                                              methoxycarbonyl                                           1100  4-amidinophenyl                                                                               (2-chlorophenyl)                                                                             OH                                                               methoxycaronyl                                            1101  4-amidinophenyl                                                                               (2-bromophenyl)                                                                              OMe                                                              methoxycarbonyl                                           1102  4-amidinophenyl                                                                               (2-bromophenyl)                                                                              OH                                                               methoxycarbonyl                                           1103  4-amidinophenyl                                                                               n-hexyloxycarbonyl                                                                           OMe                                         1104  4-amidinophenyl                                                                               n-hexyloxycarbonyl                                                                           OH                                          1105  4-amidinophenyl                                                                               isobutyloxycarbonyl                                                                          OMe                                         1106  4-amidinophenyl                                                                               isobutyloxycarbonyl                                                                          OH                                          1107  4-amidinophenyl                                                                               2-cyclopropylethoxy-                                                                         OMe                                                              carbonyl                                                  1108  4-amidinophenyl                                                                               2-cyclopropylethoxy-                                                                         OH                                                               carbonyl                                                  1110  4-amidinophenyl                                                                               2-cyclopentylethoxy-                                                                         OMe                                                              carbonyl                                                  1111  4-amidinophenyl                                                                               2-cyclopentylethoxy-                                                                         OH                                                               carbonyl                                                  1112  4-amidinophenyl                                                                               4,4,4-trifluoro-                                                                             OMe                                                              butyloxycarbonyl                                          1113  4-amidinophenyl                                                                               4,4,4-trifluoro-                                                                             OH                                                               butyloxycarbonyl                                          1114  4-amidinophenyl                                                                               n-propylsulfonyl                                                                             OH                                          1115  4-amidinophenyl                                                                               2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1116  4-amidinophenyl                                                                               4-chloro-2,5-dimethyl-                                                                       OH   536                                                         phenylsulfonyl                                            1117  4-amidinophenyl                                                                               2,3-dichlorophenyl-                                                                          OMe                                                              sulfonyl                                                  1118  4-amidinophenyl                                                                               2-bromophenyl-                                                                               OMe                                                              sulfonyl                                                  1119  4-amidinophenyl                                                                               3-bromophenyl-                                                                               OMe                                                              sulfonyl                                                  1120  4-amidinophenyl                                                                               4-bromophenyl-                                                                               OMe                                                              sulfonyl                                                  1121  4-amidinophenyl                                                                               biphenylsulfonyl                                                                             OMe                                         1122  4-amidinophenyl                                                                               5-chloro-1,3- OMe                                                              dimethyl-4-pyrazolyl                                      1123  4-amidinophenyl                                                                               3-bromo-2-    OMe                                                              thienylsulfonyl                                           1124  4-amidinophenyl                                                                               5-bromo-2-    OMe                                                              thienylsulfonyl                                           1125  4-amidinophenyl                                                                               5-[1-methyl-5-                                                                               OMe                                                              trifluoromethyl-3-                                                             pyrazolyl]-2-                                                                  thienylsulfonyl                                           1127  4-amidinophenyl                                                                               5-(3-isoxazolyl)-2-                                                                          OMe                                                              thienylsulfonyl                                           1128  4-amidinophenyl                                                                               5-(2-pyridinyl)-2-                                                                           OMe                                                              thienylsulfonyl                                           1129  4-amidinophenyl                                                                               4-methyl-2-   OMe                                                              methylcarbonylamino-                                                           5-thiazolylsulfonyl                                       1130  4-amidinophenyl                                                                               2-benzothienyl-                                                                              OMe                                                              sulfonyl                                                  1131  4-amidinophenyl                                                                               2-benzothienyl-                                                                              OMe                                                              sulfonyl                                                  1132  4-amidinophenyl                                                                               3-methyl-2-   OMe                                                              benzothienylsulfonyl                                      1133  4-amidinophenyl                                                                               8-quinolinylsulfonyl                                                                         OMe                                         1134  4-amidinophenyl                                                                               8-quinolinylsulfonyl                                                                         OH                                          1135  4-amidinophenyl                                                                               2,1,3-benzo-  OMe                                                              thiadiazol-4-ylsulfonyl                                   1136  4-amidinophenyl                                                                               2,1,3-benzo-  OH                                                               thiadiazol-4-ylsulfonyl                                   1137  4-amidinophenyl                                                                               4-N,N-dimethylamino-                                                                         OMe                                                              1-naphthylsulfonyl                                        1138  4-amidinophenyl                                                                               4-N,N-dimethylamino-                                                                         OH                                                               1-haphthylsulfonyl                                        1139  4-amidinophenyl                                                                               2,1,3-benzoxadiazol-4-                                                                       OMe                                                              ylsulfonyl                                                1140  4-amidinophenyl                                                                               2,1,3-benzoxadiazol-4-                                                                       OH                                                               ylsulfonyl                                                1141  4-amidinophenyl                                                                               2,2,5,7,8-pentamethyl                                                                        OMe                                                              3,4-dihydro-2Hbenxo-                                                           pyran-6-ylsulfonyl                                        1143  4-amidinophenyl                                                                               2,2,5,7,8-pentamethyl                                                                        OH                                                               3,4-dihydro-2Hbenzo-                                                           pyran-6-ylsulfonyl                                        1144  4-N-methylamidino                                                                             3-            OMe                                               phenyl         methylphenylsulfonyl                                      1145  4-N-ethylamidino                                                                              3-            OMe                                               phenyl         methylphenylsulfonyl                                      1146  4-N-n-propylamidino                                                                           3-            OMe                                               phenyl         methylphenylsulfonyl                                      1147  4-N-benzylamidino                                                                             3-            OMe                                               phenyl         methylphenylsulfonyl                                      1148  4-N-n-butylamidino                                                                            3-            OMe                                               phenyl         methylphenylsulfonyl                                      1149  4-N-methylamidino                                                                             3-            OH                                                phenyl         methylphenylsulfonyl                                      1150  4-N-ethylamidino                                                                              3-            OH                                                phenyl         methylphenylsulfonyl                                      1151  4-N-n-propylamidino                                                                           3-            OH                                                phenyl         methylphenylsulfonyl                                      1152  4-N-benzylamidino                                                                             3-            OH                                                phenyl         methylphenylsulfonyl                                      1153  4-N-n-butylamidino                                                                            3-            OH                                                phenyl         methylphenylsulfonyl                                      1154  4-N-methylamidino-                                                                            n-butyloxycarbonyl                                                                           OMe                                               phenyl                                                                   1155  4-N-ethylamidinophenyl                                                                        n-butyloxycarbonyl                                                                           OMe                                         1156  4-N-npropylamidino-                                                                           n-butyloxycarbonyl                                                                           OMe                                               phenyl                                                                   1157  4-N-n-butylamidino-                                                                           n-butyloxycarbonyl                                                                           OMe                                               phenyl                                                                   1158  4-N-benzylamidino-                                                                            n-butyloxycarbonyl                                                                           OMe                                               phenyl                                                                   1160  4-N-methylamidino-                                                                            n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1161  4-N-ethylamidino-                                                                             n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1162  4-N-n-propylamidino-                                                                          n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1163  4-N-n-butylamidino-                                                                           n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1164  4-N-benzylamidino-                                                                            n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1165  4-(acetoxyamidino)-                                                                           n-butyloxycarbonyl                                                                           OMe                                               phenyl                                                                   1166  4-(acetoxyamidino)-                                                                           n-butyloxycarbonyl                                                                           OH                                                phenyl                                                                   1167  4-(acetoxyamidino)-                                                                           isobutyloxycarbonyl                                                                          OMe                                               phenyl                                                                   1168  4-(acetoxyamidino)-                                                                           isobutyloxycarbonyl                                                                          OH                                                phenyl                                                                   1169  4-(acetoxyamidino)-                                                                           cyclopropylethoxy-                                                                           OMe                                               phenyl         carbonyl                                                  1170  4-(acetoxyamidino)-                                                                           cyclopropylethoxy-                                                                           OH                                                phenyl         carbonyl                                                  1171  4-(acetoxyamidino)-                                                                           benzyloxycarboyl                                                                             OMe                                               phenyl                                                                   1172  4-(acetoxyamidino)-                                                                           benzyloxycarbonyl                                                                            OH                                                phenyl                                                                   1173  4-(acetoxyamidino)-                                                                           4-            OMe                                               phenyl         methylphenylsulfonyl                                      1174  4-(acetoxyamidino)-                                                                           4-            OH                                                phenyl         methylphenylsulfonyl                                      1175  4-piperidinylethyl                                                                            n-butyloxycarbonyl                                                                           OMe                                         1176  4-piperidinylethyl                                                                            benzyloxycarbonyl                                                                            OMe                                         1177  4-piperidinylethyl                                                                            n-propyloxycarbonyl                                                                          OMe                                         1178  4-piperidinylethyl                                                                            isobutyloxycarbonyl                                                                          OMe                                         1179  4-piperidinylethyl                                                                            2-            OMe                                                              methylphenylsulfonyl                                      1180  4-piperidinylethyl                                                                            3-            OMe                                                              methylphenylsulfonyl                                      1181  4-piperidinylethyl                                                                            4-            OMe                                                              methylphenylsulfonyl                                      1182  4-piperidinylethyl                                                                            2-            OMe                                                              bromophenylsulfonyl                                       1183  4-piperidinylethyl                                                                            3-            OMe                                                              bromophenylsulfonyl                                       1184  4-piperidinylethyl                                                                            2-methoxy-                                                                     phenylsulfonyl                                            1185  4-piperidinylethyl                                                                            3-methoxy-    OMe                                                              phenylsulfonyl                                            1186  4-piperidinylethyl                                                                            3-            OMe                                                              trifluoromethylphenyl                                                          sulfonyl                                                  1187  4-piperidinylethyl                                                                            n-propylsulfonyl                                                                             OMe                                         1188  4-piperidinylethyl                                                                            n-butylsulfonyl                                                                              OMe                                         1189  4-piperidinylethyl                                                                            isopropylsulfonyl                                                                            OMe                                         1190  4-piperidinylethyl                                                                            isobutylsulfonyl                                                                             OMe                                         1191  4-piperidinylethyl                                                                            3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1192  4-piperidinylethyl                                                                            2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1193  4-piperidinylpropyl                                                                           n-butyloxycarbonyl                                                                           OMe                                         1194  4-piperidinylpropyl                                                                           n-propyloxycarbonyl                                                                          OMe                                         1195  4-piperidinylpropyl                                                                           benzyloxycarbonyl                                                                            OMe                                         1196  4-piperidinylpropyl                                                                           isobutyloxycarbonyl                                                                          OMe                                         1197  4-piperidinylpropyl                                                                           2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1198  4-piperidinylpropyl                                                                           3-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1199  4-piperidinylpropyl                                                                           4-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1200  4-piperidinylpropyl                                                                           2-            OMe                                                              bromophenylsulfonyl                                       1201  4-piperidinylpropyl                                                                           n-butylsulfonyl                                                                              OMe                                         1202  4-piperidinylpropyl                                                                           isobutylsulfonyl                                                                             OMe                                         1203  4-piperidinylpropyl                                                                           3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1204  4-piperidinylpropyl                                                                           2,4-dimethyl- OMe                                                              thiazoylsulfonyl                                          1205  4-piperidinylethyl                                                                            n-butyloxycarbonyl                                                                           OH                                          1206  4-piperidinylethyl                                                                            n-propyloxycarbonyl                                                                          OH                                          1207  4-piperidinylethyl                                                                            benyloxycarbonyl                                                                             OH                                          1208  4-piperidinylethyl                                                                            isobutyloxycarbonyl                                                                          OH                                          1209  4-piperidinylethyl                                                                            2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1210  4-piperidinylethyl                                                                            3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1211  4-piperidinylethyl                                                                            4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1212  4-piperidinylethyl                                                                            2-            OH                                                               bromophenylsulfonyl                                       1213  4-piperidinylethyl                                                                            3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1214  4-piperidinylethyl                                                                            2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1215  4-piperidinylethyl                                                                            n-butylsulfonyl                                                                              OH                                          1216  4-piperidinylethyl                                                                            isobutylsulfonyl                                                                             OH                                          1217  4-piperidinylpropyl                                                                           n-butyloxycarbonyl                                                                           OH                                          1218  4-piperidinylpropyl                                                                           n-propyloxycarbonyl                                                                          OH                                          1219  4-piperidinylpropyl                                                                           isobutyloxycarbonyl                                                                          OH                                          1220  4-piperidinylpropyl                                                                           2-methylphenyl-                                                                              OH                                                               carbonyl                                                  1221  4-piperidinylpropyl                                                                           4-methylphenyl-                                                                              OH                                                               carbonyl                                                  1222  4-piperidinylpropyl                                                                           2-bromophenyl-                                                                               OH                                                               carbonyl                                                  1223  4-piperidinylpropyl                                                                           3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1224  4-piperidinylpropyl                                                                           n-butylsulfonyl                                                                              OH                                          1225  4-piperidinylpropyl                                                                           isobutylsulfonyl                                                                             OH                                          1226  4-amidinopiperidinyl                                                                          n-butyloxycarbonyl                                                                           OMe                                         1227  4-amidinopiperidinyl                                                                          isobutyloxycarbonyl                                                                          OMe                                         1228  4-amidinopiperidinyl                                                                          n-propyloxycarbonyl                                                                          OMe                                         1229  4-amidinopiperidinyl                                                                          benzyloxycarbonyl                                                                            OMe                                         1230  4-amidinopiperidinyl                                                                          n-butylsulfonyl                                                                              OMe                                         1231  4-amidinopiperidinyl                                                                          isobutylsulfonyl                                                                             OMe                                         1232  4-amidinopiperidinyl                                                                          n-propylsulfonyl                                                                             OMe                                         1233  4-amidinopiperidinyl                                                                          2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1234  4-amidinopiperidinyl                                                                          4-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1235  4-amidinopiperidinyl                                                                          benzylsulfonyl                                                                               OMe                                         1236  4-amidinopiperidinyl                                                                          3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1237  4-amidinopiperidinyl                                                                          2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1238  4-amidinopiperidinyl                                                                          4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1239  4-amidinopiperidinyl                                                                          n-butyloxycarbonyl                                                                           OH                                          1240  4-amidinopiperidinyl                                                                          isobutyloxycarbonyl                                                                          OH                                          1241  4-amidinopiperidinyl                                                                          n-propyloxycarbonyl                                                                          OH                                          1242  4-amidinopiperidinyl                                                                          benzyloxycarbonyl                                                                            OH                                          1243  4-amidinopiperidinyl                                                                          n-butylsulfonyl                                                                              OH                                          1244  4-amidinopiperidinyl                                                                          isobutylsulfonyl                                                                             OH                                          1245  4-amidinopiperidinyl                                                                          2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1246  4-amidinopiperidinyl                                                                          3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1247  4-amidinopiperidinyl                                                                          4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1248  4-amidinopiperidinyl                                                                          2-            OH                                                               bromophenylsulfonyl                                       1249  4-amidinopiperidinyl                                                                          3-            OH                                                               bromophenylsulfonyl                                       1250  4-amidinopiperidinyl                                                                          3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1251  4-amidinopiperidinyl                                                                          2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1252  4-amidino-     n-butyloxycarbonyl                                                                           OMe                                               piperidinylmethyl                                                        1253  4-amidino-     n-propyloxycarbonyl                                                                          OMe                                               piperidinylmethyl                                                        1254  4-amidino-     benzyloxycarbonyl                                                                            OMe                                               piperidinylmethyl                                                        1255  4-amidino-     n-butylsulfonyl                                                                              OMe                                               piperidinylmethyl                                                        1256  4-amidino-     n-propylsulfonyl                                                                             OMe                                               piperidinylmethyl                                                        1257  4-amidino-     2-methylphenyl-                                                                              OMe                                               piperidinylmethyl                                                                             sulfonyl                                                  1258  4-amidino-     3-methylphenyl-                                                                              OMe                                               piperidinylmethyl                                                                             sulfonyl                                                  1259  4-amidino-     4-methylphenyl-                                                                              OMe                                               piperidinylmethyl                                                                             sulfonyl                                                  1260  4-amidino-     2-            OMe                                               piperidinylmethyl                                                                             bromophenylsulfonyl                                       1261  4-amidino-     3-            OMe                                               piperidinylmethyl                                                                             bromophenylsulfonyl                                       1262  4-amidino-     3,5-dimethyl- OMe                                               piperidinylmethyl                                                                             isoxazolylsulfonyl                                        1263  4-amidino-     4-methylphenyl-                                                                              OH                                                piperidinylmethyl                                                                             sulfonyl                                                  1264  4-amidino-     n-butyloxycarbonyl                                                                           OH                                                piperidinylmethyl                                                        1265  4-amidino-     n-propyloxycarbonyl                                                                          OH                                                piperidinylmethyl                                                        1266  4-amidino-     benzyloxycarbonyl                                                                            OH                                                piperidinylmethyl                                                        1267  4-amidino-     n-butylsulfonyl                                                                              OH                                                piperidinylmethyl                                                        1268  4-amidino-     2-methylphenyl-                                                                              OH                                                piperidinylmethyl                                                                             sulfonyl                                                  1269  4-amidino-     3-methylphenyl-                                                                              OH                                                piperidinylmethyl                                                                             sulfonyl                                                  1270  4-amidino-     2-bromophenyl-                                                                               OH                                                piperidinylmethyl                                                                             sulfonyl                                                  1271  4-amidino-     3-bromophenyl-                                                                               OH                                                piperidinylmethyl                                                                             sulfonyl                                                  1272  4-amidino-     3,5-dimethyl- OH                                                piperidinylmethyl                                                                             isoxazolylsulfonyl                                        1273  4-quinuclidinylethyl                                                                          n-butyloxycarbonyl                                                                           OH                                          1274  4-quinuclidinylethyl                                                                          n-propyloxycarbonyl                                                                          OH                                          1275  4-quinuclidinylethyl                                                                          benzyloxycarbonyl                                                                            OH                                          1276  4-quinuclidinylethyl                                                                          n-butylsulfonyl                                                                              OH                                          1277  4-quinuclidinylethyl                                                                          2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1278  4-quinuclidinylethyl                                                                          4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1279  4-quinuclidinylethyl                                                                          2-            OH                                                               bromophenylsulfonyl                                       1280  4-quinuclidinylethyl                                                                          3-            OH                                                               bromophenylsulfonyl                                       1281  4-quinuclidinylethyl                                                                          3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1282  guanidinopropyl                                                                               n-butyloxycarbonyl                                                                           OMe                                         1283  guanidinopropyl                                                                               n-propyloxycarbonyl                                                                          OMe                                         1284  guanidinopropyl                                                                               benzyloxycarbonyl                                                                            OH   435                                    1285  guanidinopropyl                                                                               n-butylsulfonyl                                                                              OMe                                         1286  guanidinopropyl                                                                               2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1287  guanidinopropyl                                                                               3-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1288  guanidinopropyl                                                                               2-            OMe                                                              bromophenylsulfonyl                                       1289  guanidinopropyl                                                                               3-            OMe                                                              bromophenylsulfonyl                                       1290  guanidinopropyl                                                                               3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1291  guanidinopropyl                                                                               benzylsulfonyl                                                                               OMe                                         1292  guanidinopropyl                                                                               styrylsulfonyl                                                                               OMe                                         1293  guanidinopropyl                                                                               2-benzothiophene-                                                                            OMe                                                              sulfonyl                                                  1294  guanidinopropyl                                                                               n-butyloxycarbonyl                                                                           OH                                          1295  guanidinopropyl                                                                               n-propyloxycarbonyl                                                                          OH                                          1296  guanidinopropyl                                                                               benzyloxycarbonyl                                                                            OH                                          1297  guanidinopropyl                                                                               n-butylsulfonyl                                                                              OH                                          1298  guanidinopropyl                                                                               2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1299  guanidinopropyl                                                                               3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1300  guanidinopropyl                                                                               4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1301  guanidinopropyl                                                                               2-            OH                                                               bromophenylsulfonyl                                       1302  guanidinopropyl                                                                               3-            OH                                                               bromophenylsulfonyl                                       1303  guanidinopropyl                                                                               3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1304  guanidinopropyl                                                                               2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1305  guanidinopropyl                                                                               benzylsulfonyl                                                                               OH                                          1306  guanidinopropyl                                                                               styrylsulfonyl                                                                               OH                                          1307  guanidinopropyl                                                                               2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1308  guanidinobutyl n-butyloxycarbonyl                                                                           OH                                          1309  guanidinobutyl n-butylsulfonyl                                                                              OH                                          1310  guanidinobutyl phenylsulfonyl                                                                               OH                                          1311  guanidinobutyl 2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1312  guanidinobutyl 4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1313  guanidinobutyl 2-            OH                                                               bromophenylsulfonyl                                       1314  guanidinobutyl 3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1315  guanidinobutyl 2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1316  guanidinobutyl benzylsulfonyl                                                                               OH                                          1317  guanidinobutyl styrylsulfonyl                                                                               OH                                          1318  guanidinobutyl 3-fluorophenyl-                                                                              OH                                                               sulfonyl                                                  1319  guanidinobutyl n-butyloxycarbonyl                                                                           OMe                                         1320  guanidinobutyl n-butylsulfonyl                                                                              OMe                                         1321  guanidinobutyl benzyloxycarbonyl                                                                            OH   449                                    1322  guanidinobutyl phenylsulfonyl                                                                               OMe                                         1323  guanidinobutyl 2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1324  guanidinobutyl 2-            OMe                                                              bromophenylsulfonyl                                       1325  guanidinobutyl 3-            OMe                                                              bromophenylsulfonyl                                       1326  guanidinobutyl 3,5-dimethyl- OMe                                                              isoxazolyl sufonyl                                        1327  guanidinobutyl benzylsulfonyl                                                                               OMe                                         1328  guanidinobutyl n-butyloxycarbonyl                                                                           OH                                          1329  guanidinobutyl isobutyloxycarbonyl                                                                          OH                                          1330  guanidinobutyl n-propyloxycarbonyl                                                                          OH                                          1331  guanidinobutyl phenylsulfonyl                                                                               OH                                          1332  guanidinobutyl n-butylsulfonyl                                                                              OH                                          1333  guanidinobutyl 2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1334  guanidinobutyl 3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1335  guanidinobutyl 4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1336  guanidinobutyl 2-            OH                                                               bromophenylsulfonyl                                       1337  4-piperidinylmethyl-                                                                          n-butyloxycarbonyl                                                                           OH                                                aminocarbonyl                                                            1338  4-piperidinylmethyl-                                                                          n-butyloxycarbonyl                                                                           OMe                                               amino-carbonyl                                                           1339  4-piperidinylmethyl-                                                                          benzyloxycarbonyl                                                                            OH                                                amino-carbonyl                                                           1340  4-piperidinylmethyl-                                                                          benzyloxycarbonyl                                                                            OMe                                               amino-carbonyl                                                           1341  4-piperidinylmethyl-                                                                          n-butylsulfonyl                                                                              OH                                                amino-carbonyl                                                           1342  4-piperidinylmethyl-                                                                          n-butylsulfonyl                                                                              OMe                                               amino-carbonyl                                                           1343  4-piperidinylmethyl-                                                                          2-methylphenyl-                                                                              OH                                                amino-carbonyl sulfonyl                                                  1344  4-piperidinylmethyl-                                                                          2-methylphenyl-                                                                              OMe                                               amino-carbonyl sulfonyl                                                  1345  4-piperidinylmethyl-                                                                          3-methylphenyl-                                                                              OH                                                amino-carobnyl sulfonyl                                                  1346  4-piperidinylmethyl-                                                                          4-methylphenyl-                                                                              OH                                                amino-carbonyl sulfonyl                                                  1347  4-piperidinylmethyl-                                                                          3-methylphenyl-                                                                              OMe                                               amino-carbonyl sulfonyl                                                  1348  4-piperidinylmethyl-                                                                          3,5-dimethyl- OH                                                amino-carbonyl isoxazolylsulfonyl                                        1349  4-piperidinylmethyl-                                                                          3,5-dimethyl- OMe                                               amino-carbonyl isoxazolylsulfonyl                                        1350  N-(4-piperidinyl-                                                                             n-butyloxycarbonyl                                                                           OH                                                methyl)-N-methyl-                                                              aminocarbonyl                                                            1351  N-(4-piperidinyl-                                                                             n-butyloxycarbonyl                                                                           OMe                                               methyl)-N-methyl-                                                              aminocarbonyl                                                            1352  N-(4-piperdinyl-                                                                              benzyloxycarbonyl                                                                            OH                                                methyl)-N-methyl-                                                              aminocarbonyl                                                            1353  N-(4-piperidinyl-                                                                             benzyloxycarbonyl                                                                            OMe                                               methyl)-N-methyl-                                                              aminocarbonyl                                                            1354  N-(4-piperidinyl-                                                                             n-butylsulfonyl                                                                              OH                                                methyl)-N-methyl-                                                              aminocarbonyl                                                            1355  N-(4-piperidinyl-                                                                             n-butylsulfonyl                                                                              OMe                                               methyl)-N-                                                                     methylaminocarbonyl                                                      1356  N-(4-piperidinyl-                                                                             2-methylphenyl-                                                                              OH                                                methyl)-N-methyl-                                                                             sulfonyl                                                        aminocarbonyl                                                            1357  N-(4-piperidinyl-                                                                             2-methylphenyl-                                                                              OMe                                               methyl)-N-methyl-                                                                             sulfonyl                                                        aminocarbonyl                                                            1358  N-(4-piperidinyl-                                                                             3-methylphenyl-                                                                              OH                                                methyl)-N-methyl-                                                                             sulfonyl                                                        aminocarbonyl                                                            1359  N-(4-N-piperidinyl-                                                                           4-methylphenyl-                                                                              OH                                                methyl)-N-methyl-                                                                             sulfonyl                                                        aminocarbonyl                                                            1360  N-(4-piperidinyl-                                                                             3-methylphenyl-                                                                              OMe                                               methyl)-N-methyl-                                                                             sulfonyl                                                        aminocarbonyl                                                            1361  N-(4-piperidinyl-                                                                             3,5-dimethyl- OH                                                methyl)-N-methyl-                                                                             isoxazolylsulfonyl                                              aminocarbonyl                                                            1362  N-(4-piperidinyl-                                                                             3,5-dimethyl- OMe                                               methyl)-N-methyl-                                                                             isoxazolylsulfonyl                                              aminocarbonyl                                                            1363  4-piperidinyl- n-butyloxycarbonyl                                                                           OH                                                aminocarbonyl                                                            1364  4-piperidinyl- 4-methylphenyl-                                                                              OH                                                aminocarbonyl  sulfonyl                                                  1365  4-guanidinophenyl                                                                             2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1366  4-guanidinophenyl                                                                             2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1367  4-guanidinophenyl                                                                             2-            OH                                                               bromophenylsulfonyl                                       1368  4-guanidinophenyl                                                                             2-            OMe                                                              bromophenylsulfonyl                                       1369  4-guanidinophenyl                                                                             3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1370  4-guanidinophenyl                                                                             3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1371  4-guanidinophenyl                                                                             3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1372  4-guanidinophenyl                                                                             2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1373  4-guanidinophenyl                                                                             2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1374  4-guanidinophenyl                                                                             benzylsulfonyl                                                                               OH                                          1375  4-guanidinophenyl                                                                             benzylsulfonyl                                                                               OMe                                         1376  4-guanidinophenyl                                                                             styrylsulfonyl                                                                               OH                                          1377  4-guanidinophenyl                                                                             styrylsulfonyl                                                                               OMe                                         1378  4-guanidinophenyl                                                                             2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1379  3-guanidinophenyl                                                                             n-butyloxycarbonyl                                                                           OH                                          1380  3-guanidinophenyl                                                                             n-butyloxycarbonyl                                                                           OMe                                         1381  3-guanidinophenyl                                                                             n-propyloxycarbonyl                                                                          OH                                          1382  3-guanidinophenyl                                                                             2-            OH                                                               bromophenylsulfonyl                                       1383  3-guanidinophenyl                                                                             2-            OMe                                                              bromophenylsulfonyl                                       1384  3-guanidinophenyl                                                                             2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1385  3-guanidinophenyl                                                                             4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1386  3-guanidinophenyl                                                                             4-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1387  3-guanidinophenyl                                                                             n-butylsulfonyl                                                                              OH                                          1388  3-guanidinophenyl                                                                             n-butylsulfonyl                                                                              OMe                                         1389  3-guanidinophenyl                                                                             styrylsulfonyl                                                                               OH                                          1390  3-guanidinophenyl                                                                             benzyloxycarbonyl                                                                            OH                                          1391  3-guanidinophenyl                                                                             benzyloxycarbonyl                                                                            OMe                                         1392  4-amidinophenylmethyl                                                                         2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1393  4-amidinophenylmethyl                                                                         2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1394  4-amidinophenylmethyl                                                                         phenylsulfonyl                                                                               OH                                          1395  4-amidinophenylmethyl                                                                         phenylsulfonyl                                                                               OMe                                         1396  4-amidinophenylmethyl                                                                         3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1397  4-amidinophenylmethyl                                                                         3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1398  4-amidinophenylmethyl                                                                         2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1399  4-amidinophenylmethyl                                                                         2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1400  4-amidinophenylmethyl                                                                         p-toluylsulfonyl                                                                             OH                                          1401  3-amidinophenylmethyl                                                                         n-butyloxycarbonyl                                                                           OH                                          1402  3-amidinophenylmethyl                                                                         n-butyloxycarbonyl                                                                           OMe                                         1403  3-amidinophenylmethyl                                                                         phenylsulfonyl                                                                               OH                                          1404  3-amidinophenylmethyl                                                                         phenylsulfonyl                                                                               OMe                                         1405  3-amidinophenylmethyl                                                                         2-            OH                                                               bromophenylsulfonyl                                       1406  3-amidinophenylmethyl                                                                         2-            OMe                                                              bromophenylsulfonyl                                       1407  3-amidinophenylmethyl                                                                         2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1408  3-amidinophenylmethyl                                                                         2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1409  3-amidinophenylmethyl                                                                         4-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1410  3-amidinophenylmethyl                                                                         4-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1411  3-amidinophenylmethyl                                                                         styrylsulfonyl                                                                               OH                                          1412  3-amidinophenylmethyl                                                                         styrylsulfonyl                                                                               OMe                                         1413  3-amidinophenylmethyl                                                                         benzyloxycarbonyl                                                                            OH                                          1414  3-amidinophenylmethyl                                                                         benzyloxycarbonyl                                                                            OMe                                         1415  3-amidinophenylmethyl                                                                         3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1416  3-amidinophenylmethyl                                                                         3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1417  3-amidinophenylmethyl                                                                         2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1418  3-amidinophenylmethyl                                                                         benzylsulfonyl                                                                               OH                                          1419  4-pyridylethyl n-benzyloxycarbonyl                                                                          OMe                                         1420  4-pyridylethyl n-benzyloxycarbonyl                                                                          OH                                          1421  4-pyridylethyl n-butyloxyoxycarbonyl                                                                        OMe                                         1422  4-pyridylethyl n-butyloxyoxycarbonyl                                                                        OH                                          1423  4-pyridylethyl 2-            OH                                                               methylphenylsulfonyl                                      1424  4-pyridylethyl 2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1425  4-pyridylethyl 2-            OH                                                               bromophenylsulfonyl                                       1426  4-pyridylethyl 2-            OMe                                                              bromophenylsulfonyl                                       1427  4-pyridylethyl 3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1428  4-pyridylethyl 3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1429  4-pyridylethyl 3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1430  4-pyridylethyl 2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1431  4-pyridylethyl 2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1432  4-pyridylethyl benzylsulfonyl                                                                               OH                                          1433  4-pyridylethyl styrylsulfonyl                                                                               OH                                          1434  4-pyridylethyl styrylsulfonyl                                                                               OMe                                         1435  4-pyridylethyl 2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1436  3-pyridylethyl n-benzyloxycarbonyl                                                                          OMe                                         1437  3-pyridylethyl n-benzyloxycarbonyl                                                                          OH                                          1438  3-pyridylethyl n-butyloxyoxycarbonyl                                                                        OMe                                         1439  3-pyridylethyl n-butyloxyoxycarbonyl                                                                        OH                                          1440  3-pyridylethyl 2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1441  3-pyridylethyl 2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1442  3-pyridylethyl 2-            OH                                                               bromophenylsulfonyl                                       1443  3-pyridylethyl 2-            OMe                                                              bromophenylsulfonyl                                       1444  3-pyridylethyl 3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1445  3-pyridylethyl 3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1446  3-pyridylethyl 3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1447  3-pyridylethyl 2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1448  3-pyridylethyl 2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1449  3-pyridylethyl benzylsulfonyl                                                                               OH                                          1450  3-pyridylethyl styrylsulfonyl                                                                               OH                                          1451  3-pyridylethyl styrylsulfonyl                                                                               OMe                                         1452  3-pyridylethyl 2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1453  2-amino-4-pyridylethyl                                                                        n-benzyloxycarbonyl                                                                          OMe                                         1454  2-amino-4-pyridylethyl                                                                        n-benzyloxycarbonyl                                                                          OH                                          1455  2-amino-4-pyridylethyl                                                                        n-butyloxyoxycarbonyl                                                                        OMe                                         1456  2-amino-4-pyridylethyl                                                                        n-butyloxyoxycarbonyl                                                                        OH                                          1457  2-amino-4-pyridylethyl                                                                        2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1458  2-amino-4-pyridylethyl                                                                        2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1459  2-amino-4-pyridylethyl                                                                        2-            OH                                                               bromophenylsulfonyl                                       1460  2-amino-4-pyridylethyl                                                                        2-            OMe                                                              bromophenylsulfonyl                                       1461  2-amino-4-pyridylethyl                                                                        3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1462  2-amino-4-pyridylethyl                                                                        3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1463  2-amino-4-pyridylethyl                                                                        3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1464  2-amino-4-pyridylethyl                                                                        2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1465  2-amino-4-pyridylethyl                                                                        2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1466  2-amino-4-pyridylethyl                                                                        benzylsulfonyl                                                                               OH                                          1467  2-amino-4-pyridylethyl                                                                        benzylsulfonyl                                                                               OMe                                         1468  2-amino-4-pyridylethyl                                                                        styrylsulfonyl                                                                               OH                                          1469  2-amino-4-pyridylethyl                                                                        styrylsulfonyl                                                                               OMe                                         1470  2-amino-4-pyridylethyl                                                                        2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1471  6-amino-3-pyridylethyl                                                                        n-benzyloxycarbonyl                                                                          OMe                                         1472  6-amino-3-pyridylethyl                                                                        n-benzyloxycarbonyl                                                                          OH                                          1473  6-amino-3-pyridylethyl                                                                        n-butyloxyoxycarbonyl                                                                        OMe                                         1474  6-amino-3-pyridylethyl                                                                        n-butyloxyoxycarbonyl                                                                        OH                                          1475  6-amino-3-pyridylethyl                                                                        2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1476  6-amino-3-pyridylethyl                                                                        2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1477  6-amino-3-pyridylethyl                                                                        2-            OH                                                               bromophenylsulfonyl                                       1478  6-amino-3-pyridylethyl                                                                        2-            OMe                                                              bromophenylsulfonyl                                       1479  6-amino-3-pyridylethyl                                                                        3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1480  6-amino-3-pyridylethyl                                                                        3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1481  6-amino-3-pyridylethyl                                                                        3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1482  6-amino-3-pyridylethyl                                                                        2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1483  6-amino-3-pyridylethyl                                                                        2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1484  6-amino-3-pyridylethyl                                                                        benzylsulfonyl                                                                               OH                                          1485  6-amino-3-pyridylethyl                                                                        benzylsulfonyl                                                                               OMe                                         1486  6-amino-3-pyridylethyl                                                                        styrylsulfonyl                                                                               OH                                          1487  6-amino-3-pyridylethyl                                                                        styrylsulfonyl                                                                               OMe                                         1488  6-amino-4-pyridylethyl                                                                        2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1489  2-amidino-4-pyridylethyl                                                                      n-benzyloxycarbonyl                                                                          OMe                                         1490  2-amidino-4-pyridylethyl                                                                      n-benzyloxycarbonyl                                                                          OH                                          1491  2-amidino-4-pyridylethyl                                                                      n-butyloxyoxycarbonyl                                                                        OMe                                         1492  2-amidino-4-pyridylethyl                                                                      n-butyloxyoxycarbonyl                                                                        OH                                          1493  2-amidino-4-pyridylethyl                                                                      2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1494  2-amidino-4-pyridylethyl                                                                      2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1495  2-amidino-4-pyridylethyl                                                                      2-            OH                                                               bromophenylsulfonyl                                       1496  2-amidino-4-pyridylethyl                                                                      2-            OMe                                                              bromophenylsulfonyl                                       1497  2-amidino-4-pyridylethyl                                                                      3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1498  2-amidino-4-pyridylethyl                                                                      3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1499  2-amidino-4-pyridylethyl                                                                      3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1500  2-amidino-4-pyridylethyl                                                                      2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1501  2-amidino-4-pyridylethyl                                                                      2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1502  2-amidino-4-pyridylethyl                                                                      benzylsulfonyl                                                                               OH                                          1503  2-amidino-4-pyridylethyl                                                                      benzylsulfonyl                                                                               OMe                                         1504  2-amidino-4-pyridylethyl                                                                      styrylsulfonyl                                                                               OH                                          1505  2-amidino-4-pyridylethyl                                                                      styrylsulfonyl                                                                               OMe                                         1506  2-amidino-4-pyridylethyl                                                                      2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1507  6-amidino-3-pyridylethyl                                                                      n-benzyloxycarbonyl                                                                          OMe                                         1508  6-amidino-3-pyridylethyl                                                                      n-benzyloxycarbonyl                                                                          OH                                          1509  6-amidino-3-pyridylethyl                                                                      n-butyloxyoxycarbonyl                                                                        OMe                                         1510  6-amidino-3-pyridylethyl                                                                      n-butyloxyoxycarbonyl                                                                        OH                                          1511  6-amidino-3-pyridylethyl                                                                      2-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1512  6-amidino-3-pyridylethyl                                                                      2-methylphenyl-                                                                              OMe                                                              sulfonyl                                                  1513  6-amidino-3-pyridylethyl                                                                      2-            OH                                                               bromophenylsulfonyl                                       1514  6-amidino-3-pyridylethyl                                                                      2-            OMe                                                              bromophenylsulfonyl                                       1515  6-amidino-3-pyridylethyl                                                                      3-methylphenyl-                                                                              OH                                                               sulfonyl                                                  1516  6-amidino-3-pyridylethyl                                                                      3,5-dimethyl- OH                                                               isoxazolylsulfonyl                                        1517  6-amidino-3-pyridylethyl                                                                      3,5-dimethyl- OMe                                                              isoxazolylsulfonyl                                        1518  6-amidino-3-pyridylethyl                                                                      2,4-dimethyl- OH                                                               thiazolylsulfonyl                                         1519  6-amidino-3-pyridylethyl                                                                      2,4-dimethyl- OMe                                                              thiazolylsulfonyl                                         1520  6-amidino-3-pyridylethyl                                                                      benzylsulfonyl                                                                               OH                                          1521  6-amidino-3-pyridylethyl                                                                      benzylsulfonyl                                                                               Me                                          1522  6-amidino-3-pyridylethyl                                                                      styrylsulfonyl                                                                               OH                                          1523  6-amidino-3-pyridylethyl                                                                      styrylsulfonyl                                                                               OMe                                         1524  6-amidino-3-pyridylethyl                                                                      2-benzothiophene-                                                                            OH                                                               sulfonyl                                                  1525  guanidinoethyl benzyloxycarbonyl                                                                            OH   421                                    ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                          ##STR360##                                                                    Ex.                                        MS                                  No.  R.sup.1 --V p.sup.1                                                                              p.sup.2                                                                            R.sup.16   Y    M +  H                              ______________________________________                                         1540 4-amidinophenyl                                                                            2     1   n-butyloxycarbonyl                                                                        OH   446                                 1541 4-amidinophenyl                                                                            2     1   3-methylphenyl-                                                                           OH   448                                                            sulfonyl                                            1542 4-amidinophenyl                                                                            1     1   benzyloxycarbonyl                                                                         OMe                                      1543 4-amidinophenyl                                                                            1     1   (2-methylphenyl)-                                                                         OH                                                                  methoxycarbonyl                                     1544 4-amidinophenyl                                                                            1     1   (3-methylphenyl)-                                                                         OH                                                                  methoxycarbonyl                                     1545 4-amidinophenyl                                                                            1     2   i-butyloxycarbonyl                                                                        OMe                                      1546 4-amidinophenyl                                                                            1     2   4-methylphenyl-                                                                           OH                                                                  sulfonyl                                            1547 4-amidinophenyl                                                                            1     2   2-methylphenyl-                                                                           OH                                                                  sulfonyl                                            1548 4-amidinophenyl                                                                            2     1   3,5-dimethylpyra-                                                                         OH                                                                  zoylsulfonyl                                        1549 4-amidinophenyl                                                                            2     1   3,5-dimethylisox-                                                                         OH                                                                  azoylsulfonyl                                       1550 4-amidinophenyl                                                                            2     1   i-butylamino-                                                                             OH                                                                  sulfonyl                                            1551 4-amidinophenyl                                                                            2     1   2-bromophenyl-                                                                            OH                                                                  sulfonyl                                            1552 4-piperidinylethyl                                                                         1     1   n-propyloxy-                                                                              OMe                                                                 carbonyl                                            1553 4-piperidinylethyl                                                                         1     2   n-butylsulfonyl                                                                           OH                                       1554 4-piperidinylethyl                                                                         1     2   (3-bromophenyl)-                                                                          OH                                                                  methylsulfony1                                      1555 4-piperidinylethyl                                                                         2     1   (3-methylphenyl)-                                                                         OMe                                                                 methoxycarbonyl                                     1556 4-piperidinylethyl                                                                         2     1   2-phenylethoxy-                                                                           OH                                                                  carbonyl                                            1557 4-(N-benzylamid-                                                                           1     1   n-butyloxycarbonyl                                                                        OH                                            ino)phenyl                                                                1558 4-[N-(2-methyl-                                                                            1     1   3-methylphenyl-                                                                           OH                                            phenyl)-methyl-       sulfonyl                                                 amidino]phenyl                                                            1559 4-[N-(2-bromo-                                                                             1     2   2-bromophenyl-                                                                            OH                                            phenyl)-methyl-       sulfonyl                                                 amidino]phenyl                                                            1560 4-(N-butyl- 2     1   3,5-dimethylpyra-                                                                         OH                                            amidino)phenyl        zoylsulfonyl                                        1561 4-[N-(2-    2     1   3-methylphenyl-                                                                           OH                                            methoxyphenyl)-       sulfonyl                                                 methyl-                                                                        amidino]phenyl                                                            1562 4-[N-(3-[trifluoro-                                                                        2     1   2,5-dimethyl-                                                                             OH                                            methyl]phen-          thiazolylsulfonyl                                        yl)methyl-                                                                     amidino]phenyl                                                            1563 4-amidino-2-                                                                               1     1   3-methylphenyl-                                                                           OH                                            fluorophenyl          sulfonyl                                            1564 4-amidino-2-                                                                               1     2   i-butylamino-                                            fluorophenyl          sulfonyl                                            1565 4-amidino-2-                                                                               2     1   3,5-dimethylisoxa-                                                                        OH                                            fluorophenyl          zoylsulfonyl                                        1566 5-amidino-2-                                                                               1     1   n-butyloxycarbonyl                                                                        OMe                                           pyridyl                                                                   1567 5-amidino-2-                                                                               1     2   2-methylphenyl-                                                                           OH                                            pyridyl               sulfonyl                                            1568 5-amidino-2-                                                                               1     2   3-methylphenyl-                                                                           OMe                                           pyridyl               sulfonyl                                            1569 5-amidino-2-                                                                               2     1   n-butylsulfonyl                                                                           OH                                            pyridyl                                                                   1570 5-amidino-2-                                                                               2     1   3,5-dimethylisoxa-                                                                        OH                                            pyridyl               zoylsulfonyl                                        1571 2-amidino-5-                                                                               1     1   2-bromophenyl-                                                                            OH                                            pyridyl               sulfonyl                                            1572 2-amidino-5-                                                                               1     1   2-(trifluoromethyl)-                                                                      OMe                                           pyridyl               phenylsulfonyl                                      1573 2-amidino-5-                                                                               1     2   n-propylamino-                                                                            OMe                                           pyridyl               carbonyl                                            1574 2-amidino-5-                                                                               1     2   4-methylphenyl-                                                                           OH                                            pyridyl               sulfonyl                                            1575 2-amidino-5-                                                                               2     1   2-fluorophenyl-                                                                           OH                                            pyridyl               sulfonyl                                            ______________________________________                                    

                                      TABLE 9                                      __________________________________________________________________________      ##STR361##                                                                    Example                             MS                                         Number                                                                              R.sup.1 -V  R.sup.16       Y   (M + H).sup.+                              __________________________________________________________________________     1585 4-piperidinylethyl                                                                         n-butyloxycarbonyl                                                                            OMe 441                                        1585A                                                                               4-piperidinylmethyl                                                                        n-butyloxycarbonyl                                                                            OH  427                                        1586 4-piperidinylethyl                                                                         benzyloxycarbonyl                                                                             OMe                                            1587 4-piperidinylethyl                                                                         n-propyloxycarbonyl                                                                           OMe                                            1588 4-piperidinylethyl                                                                         isobutyloxycarbonyl                                                                           OMe                                            1589 4-piperidinylethyl                                                                         2-methylphenylsulfonyl                                                                        OMe                                            1590 4-piperidinylethyl                                                                         3-methylphenylsulfonyl                                                                        OMe                                            1591 4-piperidinylethyl                                                                         4-methylphenylsulfonyl                                                                        OMe                                            1592 4-piperidinylethyl                                                                         2-bromophenylsulfonyl                                                                         OMe                                            1593 4-piperidinylethyl                                                                         3-bromophenylsulfonyl                                                                         OMe                                            1594 4-piperidinylethyl                                                                         2-methoxyphenyl-                                                                              OMe                                                             sulfonyl                                                      1595 4-piperidinylethyl                                                                         3-methoxyphenyl-                                                                              OMe                                                             sulfonyl                                                      1596 4-piperidinylethyl                                                                         3-trifluoromethyl-                                                                            OMe                                                             phenylsulfonyl                                                1597 4-piperidinylethyl                                                                         n-propylsulfonyl                                                                              OMe                                            1598 4-piperidinylethyl                                                                         n-butylsulfonyl                                                                               OMe                                            1599 4-piperidinylethyl                                                                         isopropylsulfonyl                                                                             OMe                                            1600 4-piperidinylethyl                                                                         isobutylsulfonyl                                                                              OMe                                            1601 4-piperidinylethyl                                                                         3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1602 4-piperidinylethyl                                                                         2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1603 4-piperidinylpropyl                                                                        n-butyloxycarbonyl                                                                            OMe 455                                        1604 4-piperidinylpropyl                                                                        n-propyloxycarbonyl                                                                           OMe                                            1605 4-piperidinylpropyl                                                                        benzyloxycarbonyl                                                                             OMe                                            1606 4-piperidinylpropyl                                                                        isobutyloxycarbonyl                                                                           OMe                                            1607 4-piperidinylpropyl                                                                        2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1608 4-piperidinylpropyl                                                                        3-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1609 4-piperidinylpropyl                                                                        4-methylphenyl-                                                                               OMe 509                                                         sulfonyl                                                      1610 4-piperidinylpropyl                                                                        2-bromophenylsulfonyl                                                                         OMe                                            1611 4-piperidinylpropyl                                                                        n-butylsulfonyl                                                                               OMe                                            1612 4-piperidinylpropyl                                                                        isobutylsulfonyl                                                                              OMe                                            1613 4-piperidinylpropyl                                                                        3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1614 4-piperidinylpropyl                                                                        2,4-dimethyl-  OMe                                                             thiazoylsulfonyl                                              1615 4-piperidinylethyl                                                                         n-butyloxycarbonyl                                                                            OH                                             1616 4-piperidinylethyl                                                                         n-propyloxycarbonyl                                                                           OH                                             1617 4-piperidinylethyl                                                                         benyloxycarbonyl                                                                              OH                                             1618 4-piperidinylethyl                                                                         isobutyloxycarbonyl                                                                           OH                                             1619 4-piperidinylethyl                                                                         2-methylphenyl-                                                                               OH  481                                                         sulfonyl                                                      1620 4-piperidinylethyl                                                                         3-methylphenyl-                                                                               OH  481                                                         sulfonyl                                                      1621 4-piperidinylethyl                                                                         4-methylphenyl-                                                                               OH  481                                                         sulfonyl                                                      1622 4-piperidinylethyl                                                                         2-bromophenylsulfonyl                                                                         OH  545                                        1623 4-piperidinylethyl                                                                         3,5-dimethyl-  OH  486                                                         isoxazolylsulfonyl                                            1624 4-piperidinylethyl                                                                         2,4-dimethyl-  OH  502                                                         thiazolylsulfonyl                                             1625 4-piperidinylethyl                                                                         n-butylsulfonyl                                                                               OH  447                                        1626 4-piperidinylethyl                                                                         isobutylsulfonyl                                                                              OH                                             1627 4-piperidinylpropyl                                                                        n-butyloxycarbonyl                                                                            OH  441                                        1628 4-piperidinylpropyl                                                                        n-propyloxycarbonyl                                                                           OH                                             1629 4-piperidinylpropyl                                                                        isobutyloxycarbonyl                                                                           OH                                             1630 4-piperidinylpropyl                                                                        2-methylphenyl-                                                                               OH                                                              carbonyl                                                      1631 4-piperidinylpropyl                                                                        4-methylphenyl-                                                                               OH  495                                                         carbonyl                                                      1632 4-piperidinylpropyl                                                                        2-bromophenyl-carbonyl                                                                        OH                                             1633 4-piperidinylpropyl                                                                        3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1634 4-piperidinylpropyl                                                                        n-butylsulfonyl                                                                               OH                                             1635 4-piperidinylpropyl                                                                        isobutylsulfonyl                                                                              OH                                             1636 4-amidinopiperidinyl                                                                       n-butyloxycarbonyl                                                                            OMe                                            1637 4-amidinopiperidinyl                                                                       isobutyloxycarbonyl                                                                           OMe                                            1638 4-amidinopiperidinyl                                                                       n-propyloxycarbonyl                                                                           OMe                                            1639 4-amidinopiperidinyl                                                                       benzyloxycarbonyl                                                                             OMe                                            1640 4-amidinopiperidinyl                                                                       n-butylsulfonyl                                                                               OMe                                            1641 4-amidinopiperidinyl                                                                       isobutylsulfonyl                                                                              OMe                                            1642 4-amidinopiperidinyl                                                                       n-propylsulfonyl                                                                              OMe                                            1643 4-amidinopiperidinyl                                                                       2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1644 4-amidinopiperidinyl                                                                       4-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1645 4-amidinopiperidinyl                                                                       benzylsulfonyl OMe                                            1646 4-amidinopiperidinyl                                                                       3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1647 4-amidinopiperidinyl                                                                       2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1648 4-amidinopiperidinyl                                                                       4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1649 4-amidinopiperidinyl                                                                       n-butyloxycarbonyl                                                                            OH                                             1650 4-amidinopiperidinyl                                                                       isobutyloxycarbonyl                                                                           OH                                             1651 4-amidinopiperidinyl                                                                       n-propyloxycarbonyl                                                                           OH                                             1652 4-amidinopiperidinyl                                                                       benzyloxycarbonyl                                                                             OH                                             1653 4-amidinopiperidinyl                                                                       n-butylsulfonyl                                                                               OH                                             1654 4-amidinopiperidinyl                                                                       isobutylsulfonyl                                                                              OH                                             1655 4-amidinopiperidinyl                                                                       2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1656 4-amidinopiperidinyl                                                                       3-methylphenyl-                                                                               OH  495                                                         sulfonyl                                                      1657 4-amidinopiperidinyl                                                                       4-methylphenyl-                                                                               OH  495                                                         sulfonyl                                                      1658 4-amidinopiperidinyl                                                                       2-bromophenylsulfonyl                                                                         OH                                             1659 4-amidinopiperidinyl                                                                       3-bromophenylsulfonyl                                                                         OH                                             1660 4-amidinopiperidinyl                                                                       3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1661 4-amidinopiperidinyl                                                                       2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1662 4-amidino-  n-butyloxycarbonyl                                                                            OMe 427                                             piperidinylmethyl                                                         1663 4-amidino-  n-propyloxycarbonyl                                                                           OMe                                                 piperidinylmethyl                                                         1664 4-amidino-  benzyloxycarbonyl                                                                             OMe                                                 piperidinylmethyl                                                         1665 4-amidino-  n-butylsulfonyl                                                                               OMe                                                 piperidinylmethyl                                                         1666 4-amidino-  n-propylsulfonyl                                                                              OMe                                                 piperidinylmethyl                                                         1667 4-amidino-  2-methylphenyl-                                                                               OMe                                                 piperidinylmethyl                                                                          sulfonyl                                                      1668 4-amidino-  3-methylphenyl-                                                                               OMe                                                 piperidinylmethyl                                                                          sulfonyl                                                      1669 4-amidino-  4-methylphenyl-                                                                               OMe                                                 piperidinylmethyl                                                                          sulfonyl                                                      1670 4-amidino-  2-bromophenylsulfonyl                                                                         OMe                                                 piperidinylmethyl                                                         1671 4-amidino-  3-bromophenylsulfonyl                                                                         OMe                                                 piperidinylmethyl                                                         1672 4-amidino-  3,5-dimethyl-  OMe                                                 piperidinylmethyl                                                                          isoxazolylsulfonyl                                            1673 4-amidino-  4-methylphenyl-                                                                               OH  509                                             piperidinylmethyl                                                                          sulfonyl                                                      1674 4-amidino-  n-butyloxycarbonyl                                                                            OH                                                  piperidinylmethyl                                                         1675 4-amidino-  n-propyloxycarbonyl                                                                           OH                                                  piperidinylmethyl                                                         1676 4-amidino-  benzyloxycarbonyl                                                                             OH                                                  piperidinylmethyl                                                         1677 4-amidino-  n-butylsulfonyl                                                                               OH                                                  piperidinylmethyl                                                         1678 4-amidino-  2-methylphenyl-                                                                               OH                                                  piperidinylmethyl                                                                          sulfonyl                                                      1679 4-amidino-  3-methylphenyl-                                                                               OH                                                  piperidinylmethyl                                                                          sulfonyl                                                      1680 4-amidino-  2-bromophenyl-sulfonyl                                                                        OH                                                  piperidinylmethyl                                                         1681 4-amidino-  3-bromophenyl-sulfonyl                                                                        OH                                                  piperidinylmethyl                                                         1682 4-amidino-  3,5-dimethyl-  OH                                                  piperidinylmethyl                                                                          isoxazolylsulfonyl                                            1683 4-quinuclidinylethyl                                                                       n-butyloxycarbonyl                                                                            OH                                             1684 4-quinuclidinylethyl                                                                       n-propyloxycarbonyl                                                                           OH                                             1685 4-quinuclidinylethyl                                                                       benzyloxycarbonyl                                                                             OH                                             1686 4-quinuclidinylethyl                                                                       n-butylsulfonyl                                                                               OH                                             1687 4-quinuclidinylethyl                                                                       2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1688 4-quinuclidinylethyl                                                                       4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1689 4-quinuclidinylethyl                                                                       2-bromophenylsulfonyl                                                                         OH                                             1690 4-quinuclidinylethyl                                                                       3-bromophenylsulfonyl                                                                         OH                                             1691 4-quinuclidinylethyl                                                                       3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1692 guanidinopropyl                                                                            n-butyloxycarbonyl                                                                            OMe                                            1693 guanidinopropyl                                                                            n-propyloxycarbonyl                                                                           OMe                                            1694 guanidinopropyl                                                                            benzyloxycarbonyl                                                                             OH  449                                        1695 guanidinopropyl                                                                            n-butylsulfonyl                                                                               OMe                                            1696 guanidinopropyl                                                                            2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1697 guanidinopropyl                                                                            3-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1698 guanidinopropyl                                                                            2-bromophenylsulfonyl                                                                         OMe                                            1699 guanidinopropyl                                                                            3-bromophenylsulfonyl                                                                         OMe                                            1700 guanidinopropyl                                                                            3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1701 guanidinopropyl                                                                            benzylsulfonyl OMe                                            1702 guanidinopropyl                                                                            styrylsulfonyl OMe                                            1703 guanidinopropyl                                                                            2-benzothiophene-                                                                             OMe                                                             sulfonyl                                                      1704 guanidinopropyl                                                                            n-butyloxycarbonyl                                                                            OH  529                                        1705 guanidinopropyl                                                                            n-propyloxycarbonyl                                                                           OH                                             1706 guanidinopropyl                                                                            benzyloxycarbonyl                                                                             OH                                             1707 guanidinopropyl                                                                            n-butylsulfonyl                                                                               OH                                             1708 guanidinopropyl                                                                            2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1709 guanidinopropyl                                                                            3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1710 guanidinopropyl                                                                            4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1711 guanidinopropyl                                                                            2-bromophenylsulfonyl                                                                         OH                                             1712 guanidinopropyl                                                                            3-bromophenylsulfonyl                                                                         OH                                             1713 guanidinopropyl                                                                            3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1714 guanidinopropyl                                                                            2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1715 guanidinopropyl                                                                            benzylsulfonyl OH                                             1716 guanidinopropyl                                                                            styrylsulfonyl OH                                             1717 guanidinopropyl                                                                            2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1718 guanidinobutyl                                                                             n-butyloxycarbonyl                                                                            OH                                             1719 guanidinobutyl                                                                             n-butylsulfonyl                                                                               OH                                             1720 guanidinobutyl                                                                             phenylsulfonyl OH                                             1721 guanidinobutyl                                                                             2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1722 guanidinobutyl                                                                             4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1723 guanidinobutyl                                                                             2-bromophenylsulfonyl                                                                         OH                                             1724 guanidinobutyl                                                                             3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1725 guanidinobutyl                                                                             2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1726 guanidinobutyl                                                                             benzylsulfonyl OH                                             1727 guanidinobutyl                                                                             styrylsulfonyl OH                                             1728 guanidinobutyl                                                                             3-fluorophenyl-                                                                               OH                                                              sulfonyl                                                      1729 guanidinobutyl                                                                             n-butyloxycarbonyl                                                                            OMe                                            1730 guanidinobutyl                                                                             n-butylsulfonyl                                                                               OMe                                            1731 guanidinobutyl                                                                             benzyloxycarbonyl                                                                             OH  463                                        1732 guanidinobutyl                                                                             phenylsulfonyl OMe                                            1733 guanidinobutyl                                                                             2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1734 guanidinobutyl                                                                             2-bromophenylsulfonyl                                                                         OMe                                            1735 guanidinobutyl                                                                             3-bromophenylsulfonyl                                                                         OMe                                            1736 guanidinobutyl                                                                             3,5-dimethyl-  OMe                                                             isoxazolyl sufonyl                                            1737 guanidinobutyl                                                                             benzylsulfonyl OMe                                            1738 guanidinobutyl                                                                             n-butyloxycarbonyl                                                                            OH                                             1739 guanidinobutyl                                                                             isobutyloxycarbonyl                                                                           OH                                             1740 guanidinobutyl                                                                             n-propyloxycarbonyl                                                                           OH                                             1741 guanidinobutyl                                                                             phenylsulfonyl OH                                             1742 guanidinobutyl                                                                             n-butylsulfonyl                                                                               OH                                             1743 guanidinobutyl                                                                             2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1744 guanidinobutyl                                                                             3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1745 guanidinobutyl                                                                             4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1746 guanidinobutyl                                                                             2-bromophenylsulfonyl                                                                         OH                                             1747 4-piperidinylmethyl-                                                                       n-butyloxycarbonyl                                                                            OH                                                  aminocarbonyl                                                             1748 4-piperidinylmethyl-                                                                       n-butyloxycarbonyl                                                                            OMe                                                 amino-carbonyl                                                            1749 4-piperidinylmethyl-                                                                       benzyloxycarbonyl                                                                             OH                                                  amino-carbonyl                                                            1750 4-piperidinylmethyl-                                                                       benzyloxycarbonyl                                                                             OMe                                                 amino-carbonyl                                                            1751 4-piperidinylmethyl-                                                                       n-butylsulfonyl                                                                               OH                                                  amino-carbonyl                                                            1752 4-piperidinylmethyl-                                                                       n-butylsulfonyl                                                                               OMe                                                 amino-carbonyl                                                            1753 4-piperidinylmethyl-                                                                       2-methylphenyl-                                                                               OH                                                  amino-carbonyl                                                                             sulfonyl                                                      1754 4-piperidinylmethyl-                                                                       2-methylphenyl-                                                                               OMe                                                 amino-carbonyl                                                                             sulfonyl                                                      1755 4-piperidinylmethyl-                                                                       3-methylphenyl-                                                                               OH                                                  amino-carbonyl                                                                             sulfonyl                                                      1756 4-piperidinylmethyl-                                                                       4-methylphenyl-                                                                               OH  510                                             amino-carbonyl                                                                             sulfonyl                                                      1757 4-piperidinylmethyl-                                                                       3-methylphenyl-                                                                               OMe                                                 amino-carbonyl                                                                             sulfonyl                                                      1758 4-piperidinylmethyl-                                                                       3,5-dimethyl-  OH                                                  amino-carbonyl                                                                             isoxazolylsulfonyl                                            1759 4-piperidinylmethyl-                                                                       3,5-dimethyl-  OMe                                                 amino-carbonyl                                                                             isoxazolylsulfonyl                                            1760 N-(4-piperidinyl-                                                                          n-butyloxycarbonyl                                                                            OH                                                  methyl)-N-methyl-                                                              aminocarbonyl                                                             1761 N-(4-piperidinyl-                                                                          n-butyloxycarbonyl                                                                            OMe                                                 methyl)-N-methyl-                                                              aminocarbonyl                                                             1762 N-(4-piperidinyl-                                                                          benzyloxycarbonyl                                                                             OH                                                  methyl)-N-methyl-                                                              aminocarbonyl                                                             1763 N-(4-piperidinyl-                                                                          benzyloxycarbonyl                                                                             OMe                                                 methyl)-N-methyl-                                                              aminocarbonyl                                                             1764 N-(4-piperidinyl-                                                                          n-butylsulfonyl                                                                               OH                                                  methyl)-N-methyl-                                                              aminocarbonyl                                                             1765 N-(4-piperidinyl-                                                                          n-butylsulfonyl                                                                               OMe                                                 methyl)-N-                                                                     methylaminocarbonyl                                                       1766 N-(4-piperidinyl-                                                                          2-methylphenyl-                                                                               OH                                                  methyl)-N-methyl-                                                                          sulfonyl                                                           aminocarbonyl                                                             1767 N-(4-piperidinyl-                                                                          2-methylphenyl-                                                                               OMe                                                 methyl)-N-methyl-                                                                          sulfonyl                                                           aminocarbonyl                                                             1768 N-(4-piperidinyl-                                                                          3-methylphenyl-                                                                               OH                                                  methyl)-N-methyl-                                                                          sulfonyl                                                           aminocarbonyl                                                             1769 N-(4-piperidinyl-                                                                          4-methylphenyl-                                                                               OH  524                                             methyl)-N-methyl-                                                                          sulfonyl                                                           aminocarbonyl                                                             1770 N-(4-piperidinyl-                                                                          3-methylphenyl-                                                                               OMe                                                 methyl)-N-methyl-                                                                          sulfonyl                                                           aminocarbonyl                                                             1771 N-(4-piperidinyl-                                                                          3,5-dimethyl-  OH                                                  methyl)-N-methyl-                                                                          isoxazolylsulfonyl                                                 aminocarbonyl                                                             1772 N-(4-piperidinyl-                                                                          3,5-dimethyl-  OMe                                                 methyl)-N-methyl-                                                                          isoxazolylsulfonyl                                                 aminocarbonyl                                                             1773 4-piperidinyl-                                                                             n-butyloxycarbonyl                                                                            OH                                                  aminocarbonyl                                                             1774 4-piperidinyl-                                                                             4-methylphenyl-                                                                               OH  496                                             aminocarbonyl                                                                              sulfonyl                                                      1775 4-guanidinophenyl                                                                          2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1776 4-guanidinophenyl                                                                          2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1777 4-guanidinophenyl                                                                          2-bromophenylsulfonyl                                                                         OH                                             1778 4-guanidinophenyl                                                                          2-bromophenylsulfonyl                                                                         OMe                                            1779 4-guanidinophenyl                                                                          3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1780 4-guanidinophenyl                                                                          3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1781 4-guanidinophenyl                                                                          3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1782 4-guanidinophenyl                                                                          2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1783 4-guanidinophenyl                                                                          2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1784 4-guanidinophenyl                                                                          benzylsulfonyl OH                                             1785 4-guanidinophenyl                                                                          benzylsulfonyl OMe                                            1786 4-guanidinophenyl                                                                          styrylsulfonyl OH                                             1787 4-guanidinophenyl                                                                          styrylsulfonyl OMe                                            1788 4-guanidinophenyl                                                                          2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1789 3-guanidinophenyl                                                                          n-butyloxycarbonyl                                                                            OH                                             1790 3-guanidinophenyl                                                                          n-butyloxycarbonyl                                                                            OMe                                            1791 3-guanidinophenyl                                                                          n-propyloxycarbonyl                                                                           OH                                             1792 3-guanidinophenyl                                                                          2-bromophenylsulfonyl                                                                         OH                                             1793 3-guanidinophenyl                                                                          2-bromophenylsulfonyl                                                                         OMe                                            1794 3-guanidinophenyl                                                                          2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1795 3-guanidinophenyl                                                                          4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1796 3-guanidinophenyl                                                                          4-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1797 3-guanidinophenyl                                                                          n-butylsulfonyl                                                                               OH                                             1798 3-guanidinophenyl                                                                          n-butylsulfonyl                                                                               OMe                                            1799 3-guanidinophenyl                                                                          styrylsulfonyl OH                                             1800 3-guanidinophenyl                                                                          benzyloxycarbonyl                                                                             OH                                             1801 3-guanidinophenyl                                                                          benzyloxycarbonyl                                                                             OMe                                            1802 4-amidinophenylmethyl                                                                      2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1803 4-amidinophenylmethyl                                                                      2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1804 4-amidinophenylmethyl                                                                      phenylsulfonyl OH                                             1805 4-amidinophenylmethyl                                                                      phenylsulfonyl OMe                                            1806 4-amidinophenylmethyl                                                                      3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1807 4-amidinophenylmethyl                                                                      3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1898 4-amidinophenylmethyl                                                                      2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1809 4-amidinophenylmethyl                                                                      2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1810 4-amidinophenylmethyl                                                                      p-toluylsulfonyl                                                                              OH                                             1811 3-amidinophenylmethyl                                                                      n-butyloxycarbonyl                                                                            OH                                             1812 3-amidinophenylmethyl                                                                      n-butyloxycarbonyl                                                                            OMe                                            1813 3-amidinophenylmethyl                                                                      phenylsulfonyl OH                                             1814 3-amidinophenylmethyl                                                                      phenylsulfonyl OMe                                            1815 3-amidinophenylmethyl                                                                      2-bromophenylsulfonyl                                                                         OH                                             1816 3-amidinophenylmethyl                                                                      2-bromophenylsulfonyl                                                                         OMe                                            1817 3-amidinophenylmethyl                                                                      2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1818 3-amidinophenylmethyl                                                                      2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1819 3-amidinophenylmethyl                                                                      4-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1820 3-amidinophenylmethyl                                                                      4-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1821 3-amidinophenylmethyl                                                                      styrylsulfonyl OH                                             1822 3-amidinophenylmethyl                                                                      styrylsulfonyl OMe                                            1823 3-amidinophenylmethyl                                                                      benzyloxycarbonyl                                                                             OH                                             1824 3-amidinophenylmethyl                                                                      benzyloxycarbonyl                                                                             OMe                                            1825 3-amidinophenylmethyl                                                                      3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1826 3-amidinophenylmethyl                                                                      3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1827 3-amidinophenylmethyl                                                                      2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1828 3-amidinophenylmethyl                                                                      benzylsulfonyl OH                                             1829 4-pyridylethyl                                                                             n-benzyloxycarbonyl                                                                           OMe                                            1830 4-pyridylethyl                                                                             n-benzyloxycarbonyl                                                                           OH                                             1831 4-pyridylethyl                                                                             n-butyloxyoxycarbonyl                                                                         OMe                                            1832 4-pyridylethyl                                                                             n-butyloxyoxycarbonyl                                                                         OH                                             1833 4-pyridylethyl                                                                             2-methylphenylsulfonyl                                                                        OH                                             1834 4-pyridylethyl                                                                             2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1835 4-pyridylethyl                                                                             2-bromophenylsulfonyl                                                                         OH                                             1836 4-pyridylethyl                                                                             2-bromophenylsulfonyl                                                                         OMe                                            1837 4-pyridylethyl                                                                             3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1838 4-pyridylethyl                                                                             3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1839 4-pyridylethyl                                                                             3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1840 4-pyridylethyl                                                                             2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1841 4-pyridylethyl                                                                             2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1842 4-pyridylethyl                                                                             benzylsulfonyl OH                                             1843 4-pyridylethyl                                                                             styrylsulfonyl OH                                             1844 4-pyridylethyl                                                                             styrylsulfonyl OMe                                            1845 4-pyridylethyl                                                                             2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1846 3-pyridylethyl                                                                             n-benzyloxycarbonyl                                                                           OMe                                            1847 3-pyridylethyl                                                                             n-benzyloxycarbonyl                                                                           OH                                             1848 3-pyridylethyl                                                                             n-butyloxyoxycarbonyl                                                                         OMe                                            1849 3-pyridylethyl                                                                             n-butyloxyoxycarbonyl                                                                         OH                                             1850 3-pyridylethyl                                                                             2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1851 3-pyridylethyl                                                                             2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1852 3-pyridylethyl                                                                             2-bromophenylsulfonyl                                                                         OH                                             1853 3-pyridylethyl                                                                             2-bromophenylsulfonyl                                                                         OMe                                            1854 3-pyridylethyl                                                                             3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1855 3-pyridylethyl                                                                             3,5-dimethyl-  OH                                             1856 3-pyridylethyl                                                                             isoxazolylsulfonyl                                                                            OMe                                                             3,5-dimethyl-                                                                  isoxazolylsulfonyl                                            1857 3-pyridylethyl                                                                             2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1858 3-pyridylethyl                                                                             2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1859 3-pyridylethyl                                                                             benzylsulfonyl OH                                             1860 3-pyridylethyl                                                                             styrylsulfonyl OH                                             1861 3-pyridylethyl                                                                             styrylsulfonyl OMe                                            1862 3-pyridylethyl                                                                             2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1863 2-amino-4-pyridylethyl                                                                     n-benzyloxycarbonyl                                                                           OMe                                            1864 2-amino-4-pyridylethyl                                                                     n-benzyloxycarbonyl                                                                           OH                                             1865 2-amino-4-pyridylethyl                                                                     n-butyloxyoxycarbonyl                                                                         OMe                                            1866 2-amino-4-pyridylethyl                                                                     n-butyloxyoxycarbonyl                                                                         OH                                             1867 2-amino-4-pyridylethyl                                                                     2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1868 2-amino-4-pyridylethyl                                                                     2-methylphenyl OMe                                                             sulfonyl                                                      1869 2-amino-4-pyridylethyl                                                                     2-bromophenylsulfonyl                                                                         OH                                             1870 2-amino-4-pyridylethyl                                                                     2-bromophenylsulfonyl                                                                         OMe                                            1871 2-amino-4-pyridylethyl                                                                     3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1872 2-amino-4-pyridylethyl                                                                     3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1873 2-amino-4-Pyridylethyl                                                                     3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1874 2-amino-4-pyridylethyl                                                                     2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1875 2-amino-4-pyridylethyl                                                                     2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1876 2-amino-4-pyridylethyl                                                                     benzylsulfonyl OH                                             1877 2-amino-4-pyridylethyl                                                                     benzylsulfonyl OMe                                            1878 2-amino-4-pyridylethyl                                                                     styrylsulfonyl OH                                             1879 2-amino-4-pyridylethyl                                                                     styrylsulfonyl OMe                                            1880 2-amino-4-pyridylethyl                                                                     2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1881 6-amino-3-pyridylethyl                                                                     n-benzyloxycarbonyl                                                                           OMe                                            1882 6-amino-3-pyridylethyl                                                                     n-benzyloxycarbonyl                                                                           OH                                             1883 6-amino-3-pyridylethyl                                                                     n-butyloxyoxycarbonyl                                                                         OMe                                            1884 6-amino-3-pyridylethyl                                                                     n-butyloxyoxycarbonyl                                                                         OH                                             1885 6-amino-3-pyridylethyl                                                                     2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1886 6-amino-3-pyridylethyl                                                                     2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1887 6-amino-3-pyridylethyl                                                                     2-bromophenylsulfonyl                                                                         OH                                             1888 6-amino-3-pyridylethyl                                                                     2-bromophenylsulfonyl                                                                         OMe                                            1889 6-amino-3-pyridylethyl                                                                     3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1890 6-amino-3-pyridylethyl                                                                     3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1891 6-amino-3-pyridylethyl                                                                     3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1892 6-amino-3-pyridylethyl                                                                     2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1893 6-amino-3-pyridylethyl                                                                     2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1894 6-amino-3-pyridylethyl                                                                     benzylsulfonyl OH                                             1895 6-amino-3-pyridylethyl                                                                     benzylsulfonyl OMe                                            1896 6-amino-3-pyridylethyl                                                                     styrylsulfonyl OH                                             1897 6-amino-3-pyridylethyl                                                                     styrylsulfonyl OMe                                            1898 6-amino-4-pyridylethyl                                                                     2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1899 2-amidino-4-pyridylethyl                                                                   n-benzyloxycarbonyl                                                                           OMe                                            1900 2-amidino-4-pyridylethyl                                                                   n-benzyloxycarbonyl                                                                           OH                                             1901 2-amidino-4-pyridylethyl                                                                   n-butyloxyoxycarbonyl                                                                         OMe                                            1902 2-amidino-4-pyridylethyl                                                                   n-butyloxyoxycarbonyl                                                                         OH                                             1903 2-amidino-4-pyridylethyl                                                                   2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1904 2-amidino-4-pyridylethyl                                                                   2-methylphenyl-                                                                               OMe                                                             sulfonyl                                                      1905 2-amidino-4-pyridylethyl                                                                   2-bromophenylsulfonyl                                                                         OH                                             1906 2-amidino-4-pyridylethyl                                                                   2-bromophenylsulfonyl                                                                         OMe                                            1907 2-amidino-4-pyridylethyl                                                                   3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1908 2-amidino-4-pyridylethyl                                                                   3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1909 2-amidino-4-pyridylethyl                                                                   3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1910 2-amidino-4-pyridylethyl                                                                   2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1911 2-amidino-4-pyridylethyl                                                                   2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1912 2-amidino-4-pyridylethyl                                                                   benzylsulfonyl OH                                             1913 2-amidino-4-pyridylethyl                                                                   benzylsulfonyl OMe                                            1914 2-amidino-4-pyridylethyl                                                                   styrylsulfonyl OH                                             1915 2-amidino-4-pyridylethyl                                                                   styrylsulfonyl OMe                                            1916 2-amidino-4-pyridylethyl                                                                   2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1917 6-amidino-3-pyridylethyl                                                                   n-benzyloxycarbonyl                                                                           OMe                                            1918 6-amidino-3-pyridylethyl                                                                   n-benzyloxycarbonyl                                                                           OH                                             1919 6-amidino-3-pyridylethyl                                                                   n-butyloxyoxycarbonyl                                                                         OMe                                            1920 6-amidino-3-pyridylethyl                                                                   n-butyloxyoxycarbonyl                                                                         OH                                             1921 6-amidino-3-pyridylethyl                                                                   2-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1922 6-amidino-3-pyridylethyl                                                                   2-methylphenyl-                                                                               OMe                                            1923 6-amidino-3-pyridylethyl                                                                   2-bromophenylsulfonyl                                                                         OH                                             1924 6-amidino-3-pyridylethyl                                                                   2-bromophenylsulfonyl                                                                         OMe                                            1925 6-amidino-3-pyridylethyl                                                                   3-methylphenyl-                                                                               OH                                                              sulfonyl                                                      1926 6-amidino-3-pyridylethyl                                                                   3,5-dimethyl-  OH                                                              isoxazolylsulfonyl                                            1927 6-amidino-3-pyridylethyl                                                                   3,5-dimethyl-  OMe                                                             isoxazolylsulfonyl                                            1928 6-amidino-3-pyridylethyl                                                                   2,4-dimethyl-  OH                                                              thiazolylsulfonyl                                             1929 6-amidino-3-pyridylethyl                                                                   2,4-dimethyl-  OMe                                                             thiazolylsulfonyl                                             1930 6-amidino-3-pyridylethyl                                                                   benzylsulfonyl OH                                             1931 6-amidino-3-pyridylethyl                                                                   benzylsulfonyl Me                                             1932 6-amidino-3-pyridylethyl                                                                   styrylsulfonyl OH                                             1933 6-amidino-3-pyridylethyl                                                                   styrylsulfonyl OMe                                            1934 6-amidino-3-pyridylethyl                                                                   2-benzothiophene-                                                                             OH                                                              sulfonyl                                                      1935 4-amidino-2-fluoro-                                                                        2-methylphenylsulfonyl                                                                        OH                                                  phenyl                                                                    1936 4-amidino-2-fluoro-                                                                        3,5-dimethylisoxazolyl-                                                                       OH                                                  phenyl      sulfonyl                                                      1937 2-amidino-5-pyridyl                                                                        2-methylphenylsulfonyl                                                                        OH                                             1938 2-amidino-5-pyridyl                                                                        2-bromophenylsulfonyl                                                                         OH                                             1939 2-amidino-5-pyridyl                                                                        i-butyloxycarbonyl                                                                            OMe                                            1940 2-amidino-5-pyridyl                                                                        3,5-dimethylisoxazolyl-                                                                       OH                                                              sulfonyl                                                      1941 3-amidino-6-pyridyl                                                                        2-methylphenylsulfonyl                                                                        OH                                             1942 3-amidino-6-pyridyl                                                                        2-bromophenylsulfonyl                                                                         OMe                                            1943 3-amidino-6-pyridyl                                                                        2,5-dimethylthiazolyl-                                                                        OH                                                              sulfonyl                                                      1944 3-amidino-6-pyridyl                                                                        3,5-dimethylisoxazolyl-                                                                       OH                                                              sulfonyl                                                      1945 4-piperidinylethyl                                                                         3-methylphenylsulfonyl                                                                        OH  481                                        1946 4-(N-2-methoxybenzyl)-                                                                     2-methylphenylsulfonyl                                                                        OMe 622.3                                           amidinophenyl HCl                                                         1947 4-(N-2-methoxybenzyl)-                                                                     2-methylphenylsulfonyl                                                                        OH  608.3                                           amidinophenyl TFA                                                         1948 4-(N-n-butyl)-                                                                             2-methylphenylsulfonyl                                                                        OMe 558.4                                           amidinophenyl                                                             1949 4-(N-n-butyl)-                                                                             2-methylphenylsulfonyl                                                                        OH  544.4                                           amidinophenyl                                                             1950 4-(N-ethyl)-                                                                               2-methylphenylsulfonyl                                                                        OMe 530.3                                           amidinophenyl                                                             1951 4-(N-ethyl)-                                                                   amidinophenyl                                                                              2-methylphenylsulfonyl                                                                        OH  516.3                                      1952 4-amidinophenoxymethyl                                                                     benzyloxycarbonyl                                                                             OMe                                            1953 4-amidinophenoxymethyl                                                                     benzyloxycarbonyl                                                                             OH                                             1954 4-amidinophenoxymethyl                                                                     n-butyloxycarbonyl                                                                            OMe                                            1955 4-amidinophenoxymethyl                                                                     n-butyloxycarbonyl                                                                            OH                                             1956 4-amidinophenoxymethyl                                                                     cyclopropylethoxy                                                                             OMe                                                             carbonyl                                                      1957 4-amidinophenoxymethyl                                                                     cyclopropylethoxy                                                                             OH                                                              carbonyl                                                      1958 4-amidinophenoxymethyl                                                                     4-methylphenylsulfonyl                                                                        OMe                                            1959 4-amidinophenoxymethyl                                                                     4-methylphenylsulfonyl                                                                        OH                                             1960 4-amidinophenoxymethyl                                                                     3-methylphenylsulfonyl                                                                        OMe                                            1961 4-amidinophenoxymethyl                                                                     3-methylphenylsulfonyl                                                                        OH                                             1962 4-amidinophenoxymethyl                                                                     n-butylsulfonyl                                                                               OMe                                            1963 4-amidinophenoxymethyl                                                                     n-butylsulfonyl                                                                               OH                                             1964 4-amidinophenoxy                                                                           benzyloxycarbonyl                                                                             OMe                                            1965 4-amidinophenoxy                                                                           benzyloxycarbonyl                                                                             OH                                             1967 4-amidinophenoxy                                                                           n-butyloxycarbonyl                                                                            OMe                                            1968                                                                           1969 4-amidinophenoxy                                                                           n-butyloxycarbonyl                                                                            OH                                             1970 4-amidinophenoxy                                                                           cyclopropylethyoxy                                                                            OHe                                                             carbonyl                                                      1971 4-amidinophenoxy                                                                           cyclopropylethoxy                                                                             OH                                             1972 4-amidinophenoxy                                                                           carbonyl                                                                       4-methylphenylsulfonyl                                                                        OMe                                            1973 4-amidinophenoxy                                                                           4-methylphenylsulfonyl                                                                        OH                                             1974 4-amidinophenoxy                                                                           3-methylphenylsulfonyl                                                                        OMe                                            1975 4-amidinophenoxy                                                                           3-methylphenylsulfonyl                                                                        OH                                             1976 4-amidinophenoxy                                                                           n-butylsulfonyl                                                                               OMe                                            1977 4-amidinophenoxy                                                                           n-butylsulfonyl                                                                               OH                                             1978 4-amidinophenethyl                                                                         benzyloxycarbonyl                                                                             OMe                                            1979 4-amidinophenethyl                                                                         benzyloxycarbonyl                                                                             OH                                             1980 4-amidinophenethyl                                                                         n-butyloxycarbonyl                                                                            OMe                                            1981 4-amidinophenethyl                                                                         n-butyloxycarbonyl                                                                            OH                                             1982 4-amidinophenethyl                                                                         cyclopropylethoxy                                                                             OMe                                                             carbonyl                                                      1983 4-amidinophenethyl                                                                         cyclopropylethoxy                                                                             OH                                                              carbonyl                                                      1984 4-amidinophenethyl                                                                         4-methylphenylsulfonyl                                                                        OMe                                            1985 4-amidinophenethyl                                                                         4-methylphenylsulfonyl                                                                        OH                                             1986 4-amidinophenethyl                                                                         3-methylphenylsulfonyl                                                                        OMe                                            1987 4-amidinophenethyl                                                                         3-methylphenylsulfonyl                                                                        OH                                             1988 4-amidinophenethyl                                                                         n-butylsulfonyl                                                                               OMe                                            1989 4-amidinophenethyl                                                                         n-butylsulfonyl                                                                               OH                                             1990 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OMe                                                 aminomethyl                                                               1991 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OH                                                  aminomethyl                                                               1993 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OMe                                                 aminomethyl                                                               1994 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OH                                                  aminomethyl                                                               1995 N-(4-amidinophenyl)                                                                        cyclopropylethoxy                                                                             OH                                                  aminomethyl carbonyl                                                      1996 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OMe                                                 aminomethyl                                                               1997 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OH                                                  aminomethyl                                                               1998 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OMe                                                 aminomethyl                                                               1999 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OH                                                  aminomethyl                                                               2000 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OMe                                                 aminomethyl                                                               2001 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OH                                                  aminomethyl                                                               2002 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OMe                                                 methylamino                                                               2003 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OH                                                  methylamino                                                               2004 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OMe                                                 methylamino                                                               2005 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OH                                                  methylamino                                                               2006 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OMe                                                 methylamino carbonyl                                                      2007 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OH                                                  methylamino carbonyl                                                      2008 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OMe                                                 methylamino                                                               2010 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OH                                                  methylamino                                                               2011 4-amidinophenyl                                                                            3-methylphenylsulfonyl                                                                        OMe                                                 methylamino                                                               2012 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OMe                                                 methylamino                                                               2013 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OH                                                  methylamino                                                               2014 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OMe                                                 aminocarbonyl                                                             2015 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OH                                                  aminocarbonyl                                                             2016 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OMe                                                 aminocarbonyl                                                             2017 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OH                                                  aminocarbonyl                                                             2018 N-(4-amidinophenyl)                                                                        cyclopropylethoxy                                                                             OMe                                                 aminocarbonyl                                                                              carbonyl                                                      2019 N-(4-amidinophenyl)                                                                        cyclopropylethoxy                                                                             OH                                                  aminocarbonyl                                                                              carbonyl                                                      2020 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OMe                                                 aminocarbonyl                                                             2021 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OH                                                  aminocarbonyl                                                             2022 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OMe                                                 aminocarbonyl                                                             2023 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OH                                                  aminocarbonyl                                                             2024 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OMe                                                 aminocarbonyl                                                             2025 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OH                                                  aminocarbonyl                                                             2027 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OMe                                                 carbonylamino                                                             2028 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OH                                                  carbonylamino                                                             2029 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OMe                                                 carbonylamino                                                             2030 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OH                                                  carbonylamino                                                             2031 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OMe                                                 carbonylamino                                                                              carbonyl                                                      2032 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OH                                                  carbonylamino                                                                              carbonyl                                                      2033 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OMe                                                 carbonylamino                                                             2034 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OH                                                  carbonylamino                                                             2035 4-amidinophenyl                                                                            3-methylphenylsulfonyl                                                                        OMe                                                 carbonylamino                                                             2036 4-amidinophenyl                                                                            3-methylphenylsulfonyl                                                                        OH                                                  carbonylamino                                                             2037 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OMe                                                 carbonylamino                                                             2038 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OH                                                  carbonylamino                                                             2039 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OMe                                                 amino                                                                     2040 N-(4-amidinophenyl)                                                                        benzyloxycarbonyl                                                                             OH                                                  amino                                                                     2041 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OMe                                                 amino                                                                     2042 N-(4-amidinophenyl)                                                                        n-butyloxycarbonyl                                                                            OH                                                  amino                                                                     2044 N-(4-amidinophenyl)                                                                        cyclopropylethoxy                                                                             OMe                                                 amino       carbonyl                                                      2045 N-(4-amidinophenyl)                                                                        cyclopropylethoxy                                                                             OH                                                  amino       carbonyl                                                      2046 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OMe                                                 amino                                                                     2047 N-(4-amidinophenyl)                                                                        4-methylphenylsulfonyl                                                                        OH                                                  amino                                                                     2048 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OMe                                                 amino                                                                     2049 N-(4-amidinophenyl)                                                                        3-methylphenylsulfonyl                                                                        OH                                                  amino                                                                     2050 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OMe                                                 amino                                                                     2051 N-(4-amidinophenyl)                                                                        n-butylsulfonyl                                                                               OH                                                  amino                                                                     2052 N-(4-amidinophenyl)-N-                                                                     benzyloxycarbonyl                                                                             OMe                                                 methylamino                                                               2053 N-(4-amidinophenyl)-N-                                                                     benzyloxycarbonyl                                                                             OH                                                  methylamino                                                               2054 N-(4-amidinophenyl)-N-                                                                     n-butyloxycarbonyl                                                                            OMe                                                 methylamino                                                               2055 N-(4-amidinophenyl)-N-                                                                     n-butyloxycarbonyl                                                                            OH                                                  methylamino                                                               2056 N-(4-amidinophenyl)-N-                                                                     cyclopropylethoxy                                                                             OMe                                                 methylamino carbonyl                                                      2057 N-(4-amidinophenyl)-N-                                                                     cyclopropylethoxy                                                                             OH                                                  methylamino carbonyl                                                      2058 N-(4-amidinophenyl)-N-                                                                     4-methylphenylsulfonyl                                                                        OMe                                                 methylamino                                                               2059 N-(4-amidinophenyl)-N-                                                                     4-methylphenylsulfonyl                                                                        OH                                                  methylamino                                                               2061 N-(4-amidinophenyl)-N-                                                                     3-methylphenylsulfonyl                                                                        OMe                                                 methylamino                                                               2062 N-(4-amidinophenyl)-N-                                                                     3-methylphenylsulfonyl                                                                        OH                                                  methylamino                                                               2063 N-(4-amidinophenyl)-N-                                                                     n-butylsulfonyl                                                                               OMe                                                 methylamino                                                               2064 N-(4-amidinophenyl)-N-                                                                     n-butylsulfonyl                                                                               OH                                                  methylamino                                                               2065 4-amidinobenzoyl                                                                           benzyloxycarbonyl                                                                             OMe                                            2066 4-amidinobenzoyl                                                                           benzyloxycarbonyl                                                                             OH                                             2067 4-amidinobenzoyl                                                                           n-butyloxycarbonyl                                                                            OMe                                            2068 4-amidinobenzoyl                                                                           n-butyloxycarbonyl                                                                            OH                                             2069 4-amidinobenzoyl                                                                           cyclopropylethoxy                                                                             OMe                                                             carbonyl                                                      2070 4-amidinobenzoyl                                                                           cyclopropylethoxy                                                                             OH                                                              carbonyl                                                      2071 4-amidinobenzoyl                                                                           4-methylphenylsulfonyl                                                                        OMe                                            2072 4-amidinobenzoyl                                                                           4-methylphenylsulfonyl                                                                        OH                                             2073 4-amidinobenzoyl                                                                           3-methylphenylsulfonyl                                                                        OMe                                            2074 4-amidinobenzoyl                                                                           3-methylphenylsulfonyl                                                                        OH                                             2075 4-amidinobenzoyl                                                                           n-butylsulfonyl                                                                               OMe                                            2076 4-amidinobenzoyl                                                                           n-butylsulfonyl                                                                               OH                                             2077 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OMe                                                 methylcarbonyl                                                            2078 4-amidinophenyl                                                                            benzyloxycarbonyl                                                                             OH                                                  methylcarbonyl                                                            2079 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OMe                                                 methylcarbonyl                                                            2080 4-amidinophenyl                                                                            n-butyloxycarbonyl                                                                            OH                                                  methylcarbonyl                                                            2081 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OMe                                                 methylcarbonyl                                                                             carbonyl                                                      2083 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OH                                                  methylcarbonyl                                                                             carbonyl                                                      2084 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OMe                                                 methylcarbonyl                                                            2085 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OH                                                  methylcarbonyl                                                            2086 4-amidinophenyl                                                                            3-methylphenylsulfonyl                                                                        OMe                                                 methylcarbonyl                                                            2087 4-amidinophenyl                                                                            3-methylphenylsulfonyl                                                                        OH                                                  methylcarbonyl                                                            2088 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OMe                                                 methylcarbonyl                                                            2089 4-amidinophenyl                                                                            n-butylsulfonyl                                                                               OH                                                  methylcarbonyl                                                            2090 4-amidinophenyl-                                                                           benzyloxycarbonyl                                                                             OMe                                                 carbonylmethyl                                                            2091 4-amidinophenyl-                                                                           benzyloxycarbonyl                                                                             OH                                                  carbonylmethyl                                                            2092 4-amidinophenyl-                                                                           n-butyloxycarbonyl                                                                            OMe                                                 carbonylmethyl                                                            2093 4-amidinophenyl-                                                                           n-butyloxycarbonyl                                                                            OH                                                  carbonylmethyl                                                            2094 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OMe                                                 carbonylmethyl                                                                             carbonyl                                                      2095 4-amidinophenyl                                                                            cyclopropylethoxy                                                                             OH                                                  carbonylmethyl                                                                             carbonyl                                                      2096 4-amidinophenyl                                                                            4-methylphenylsulfonyl                                                                        OMe                                                 carbonylmethyl                                                            2097 4-amidinophenyl-                                                                           4-methylphenylsulfonyl                                                                        OH                                                  carbonylmethyl                                                            2098 4-amidinophenyl-                                                                           3-methylphenylsulfonyl                                                                        OMe                                                 carbonylmethyl                                                            2100 4-amidinophenyl-                                                                           3-methylphenylsulfonyl                                                                        OH                                                  carbonylmethyl                                                            2101 4-amidinophenyl-                                                                           n-butylsulfonyl                                                                               OMe                                                 carbonylmethyl                                                            2102 4-amidinophenyl-                                                                           n-butylsulfonyl                                                                               OH                                                  carbonylmethyl                                                            2103 4-amidinophenyl                                                                            3,5-dimethylisoxazol-                                                                         OMe HNMR                                            HOAc salt, 5(R),N.sup.2 (S)                                                                4-ylsulfonyl                                                       isomer                                                                    2104 4-amidinophenyl                                                                            3,5-dimethylisoxazol-                                                                         OH  493                                             TFA salt, 5(R),N.sup.2 (S)                                                                 4-ylsulfonyl                                                       isomer                                                                    2105 4-amidinophenyl                                                                            3,5-dimethylisoxazol                                                                          OMe HNMR                                            HOAc salt, 5(S),N.sup.2 (S)                                                                4-ylsulfonyl                                                       isomer                                                                    2106 4-amidinophenyl                                                                            3,5-dimethylisoxazol-                                                                         OH                                                  TFA salt, 5(S),N.sup.2 (S)                                                                 4-ylsulfonyl                                                       isomer                                                                    2107 4-amidinophenyl                                                                            3,5-dimethylisoxazol-                                                                         OMe                                                 HOAc salt, 5(R),N.sup.2 (R)                                                                4-ylsulfonyl                                                       isomer                                                                    2108 4-amidinophenyl                                                                            3,5-dimethylisoxazol                                                                          OMe                                                 HOAc salt, 5(S),N.sup.2 (R)                                                                4-ylsulfonyl                                                       isomer                                                                    2109 2-guanidinoethyl                                                                           carbobenzyloxy OH  435                                        2110 5-guanidinovaleryl                                                                         carbobenzyloxy OH  477                                        2111 4-(N-2-     2-methylphenylsulfonyl                                                                        OMe 622                                             methoxybenyzyl)-                                                               amidinophenyl ·HCl                                               2112 4-(N-2-                                                                        methoxybenyzyl)-                                                                           2-methylphenylsulfonyl                                                                        OH  608                                             amidinophenyl ·HCl                                               2113 4-(N-n-butyl)-                                                                             2-methylphenylsulfonyl                                                                        OMe 558                                             amidinophenyl ·TFA                                               2114 4-(N-n-butyl)-                                                                             2-methylphenylsulfonyl                                                                        OH  544                                             amidinophenyl ·TFA                                               2115 4-(N-ethyl)-                                                                               2-methylphenylsulfonyl                                                                        OMe 530                                             amidinophenyl ·TFA                                               2116 4-(N-ethyl)-                                                                               2-methylphenylsulfonyl                                                                        OH  516                                             amidinophenyl ·TFA                                               2117 4-amidinophenyl                                                                            4-methyl-2-methylcarbonylamino-                                                               OH  566                                                         5-thiazolylsulfonyl ·TFA                             2118 4-amidinophenyl                                                                            5-phenylsulfonyl-2-                                                                           OMe 634                                                         thienylsulfonyl·TFA                                  2119 4-amidinophenyl                                                                            5-phenylsulfonyl-2-                                                                           OMe 620                                                         thienylsulfonyl·TFA                                  2120 N-t-butyloxycarbonyl-4-                                                                    5-phenylsulfonyl-2-                                                                           OH  720                                             amidinophenyl                                                                              thienylsulfonyl·TFA                                  __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________      ##STR362##                                                                    Ex.                                 MS                                         No. R.sup.1 --V                                                                               R.sup.5a                                                                            R.sup.16     Y  (M +  H)                                   __________________________________________________________________________     2121                                                                               4-piperidinylethyl                                                                        methyl                                                                              benzyloxycarbonyl                                                                           OH                                            2122                                                                               4-piperidinylethyl                                                                        methyl                                                                              2-methylphenylsulfonyl                                                                      OH                                            2123                                                                               4-piperidinylethyl                                                                        methyl                                                                              3,5-dimethylisoxazolyl                                                                      OH                                                                sulfonyl                                                   2124                                                                               4-piperidinylethyl                                                                        methyl                                                                              n-butylsulfonyl                                                                             OH                                            2125                                                                               4-piperidinylethyl                                                                        methyl                                                                              n-butylsulfonyl                                                                             OMe                                           2126                                                                               4-piperidinylmethyl                                                                       methyl                                                                              n-butylsulfonyl                                                                             OH                                            2127                                                                               4-piperidinylmethyl                                                                       methyl                                                                              n-butylsulfonyl                                                                             OMe                                           2128                                                                               4-piperidinylmethyl                                                                       methyl                                                                              2-methylphenylsulfonyl                                                                      OH                                            2129                                                                               4-piperidinylmethyl                                                                       methyl                                                                              2-bromophenylsulfonyl                                                                       OH                                            2130                                                                               4-piperidinylmethyl                                                                       methyl                                                                              3-methylphenylsulfonyl                                                                      OH                                            2131                                                                               4-piperidinylmethyl                                                                       methyl                                                                              3-methylphenylsulfonyl                                                                      OMe                                           2132                                                                               4-piperidinylmethyl                                                                       methyl                                                                              3,5-dimethylisoxazolyl                                                                      OH                                                                sulfonyl                                                   2133                                                                               4-piperidinylmethyl                                                                       methyl                                                                              3,5-dimethylisoxazolyl                                                                      OMe                                                               sulfonyl                                                   2134                                                                               4-piperidinylmethyl                                                                       methyl                                                                              styrylsulfonyl                                                                              OH                                            2135                                                                               4-piperidinylmethyl                                                                       methyl                                                                              benzyloxycarbonyl                                                                           OH                                            2136                                                                               4-piperidinylmethyl                                                                       methyl                                                                              benzyloxycarbonyl                                                                           OMe                                           2137                                                                               4-piperidinylmethyl                                                                       methyl                                                                              n-butyloxycarbonyl                                                                          OH                                            2138                                                                               4-piperidinylmethyl                                                                       methyl                                                                              n-butyloxycarbonyl                                                                          OMe                                           2139                                                                               4-piperidinylpropyl                                                                       methyl                                                                              n-butylsulfonyl                                                                             OH                                            2140                                                                               4-piperidinylpropyl                                                                       methyl                                                                              n-butylsulfonyl                                                                             OMe                                           2141                                                                               4-piperidinylpropyl                                                                       methyl                                                                              2-methylphenylsulfonyl                                                                      OH                                            2142                                                                               4-piperidinylpropyl                                                                       methyl                                                                              2-bromophenylsulfonyl                                                                       OH                                            2143                                                                               4-piperidinylpropyl                                                                       methyl                                                                              3-methylphenylsulfonyl                                                                      OH                                            2144                                                                               4-piperidinylpropyl                                                                       methyl                                                                              3-methylphenylsulfonyl                                                                      OMe                                           2145                                                                               4-piperidinylpropyl                                                                       methyl                                                                              3,5-dimethylisoxazolyl                                                                      OH                                                                sulfonyl                                                   2146                                                                               4-piperidinylpropyl                                                                       methyl                                                                              3,5-dimethylisoxazolyl                                                                      OMe                                                               sulfonyl                                                   2147                                                                               4-piperidinylpropyl                                                                       methyl                                                                              styrylsulfonyl                                                                              OH                                            2148                                                                               4-piperidinylpropyl                                                                       methyl                                                                              benzyloxycarbonyl                                                                           OH                                            2149                                                                               4-piperidinylpropyl                                                                       methyl                                                                              benzyloxycarbonyl                                                                           OMe                                           2150                                                                               4-piperidinylpropyl                                                                       methyl                                                                              n-butyloxycarbonyl                                                                          OH                                            2151                                                                               4-piperidinylpropyl                                                                       methyl                                                                              n-butyloxycarbonyl                                                                          OMe                                           2152                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              n-butylsulfonyl                                                                             OH                                            2153                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              n-butylsulfonyl                                                                             OMe                                           2154                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              2-methylphenylsulfonyl                                                                      OH                                            2155                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              2-bromophenylsulfonyl                                                                       OH                                            2156                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              3-methylphenylsulfonyl                                                                      OH                                            2157                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              3-methylphenylsulfonyl                                                                      OMe                                           2158                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              3,5-dimethylisoxazolyl                                                                      OH                                                                sulfonyl                                                   2159                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              3,5-dimethylisoxazolyl                                                                      OMe                                                               sulfonyl                                                   2160                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              styrylsulfonyl                                                                              OH                                            2161                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              benzyloxycarbonyl                                                                           OH .                                          2162                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              benzyloxycarbonyl                                                                           OMe                                           2163                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              n-butyloxycarbonyl                                                                          OH                                            2164                                                                               4-amidinopiperidinyl                                                                      methyl                                                                              n-butyloxycarbonyl                                                                          OMe                                           2165                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              n-butylsulfonyl                                                                             OH                                                methyl                                                                     2166                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              n-butylsulfonyl                                                                             OMe                                               methyl                                                                     2167                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              2-methylphenylsulfonyl                                                                      OH                                                methyl                                                                     2168                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              2-bromophenylsulfonyl                                                                       OH                                                methyl                                                                     2169                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              3-methylphenylsulfonyl                                                                      OH                                                methyl                                                                     2170                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              3-methylphenylsulfonyl                                                                      OMe                                               methyl                                                                     2171                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              3,5-dimethylisoxazolyl                                                                      OH                                                methyl          sulfonyl                                                   2172                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              3,5-dimethylisoxazolyl                                                                      OMe                                               methyl          sulfonyl                                                   2173                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              styrylsulfonyl                                                                              OH                                                methyl                                                                     2174                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              benzyloxycarbonyl                                                                           OH                                                methyl                                                                     2175                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              benzyloxycarbonyl                                                                           OMe                                               methyl                                                                     2176                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              n-butyloxycarbonyl                                                                          OH                                                methyl                                                                     2177                                                                               4-amidinopiperidinyl-                                                                     methyl                                                                              n-butyloxycarbonyl                                                                          OMe                                               methyl                                                                     2178                                                                               4-amidinophenyl                                                                           methyl                                                                              phenylcarbonyl                                                                              OMe                                           2179                                                                               4-amidinophenyl                                                                           methyl                                                                              phenylcarbonyl                                                                              OH                                            2180                                                                               4-amidinophenyl                                                                           methyl                                                                              2,6-methylphenylcarbonyl                                                                    OMe                                           2181                                                                               4-amidinophenyl                                                                           methyl                                                                              2,6-methylphenylcarbonyl                                                                    OH                                            2182                                                                               4-amidinophenyl                                                                           methyl                                                                              2-methylphenylcarbonyl                                                                      OMe                                           2183                                                                               4-amidinophenyl                                                                           methyl                                                                              2-methylphenylcarbonyl                                                                      OH                                            2184                                                                               4-amidinophenyl                                                                           methyl                                                                              2-bromophenylcarbonyl                                                                       OMe                                           2185                                                                               4-amidinophenyl                                                                           methyl                                                                              2-bromophenylcarbonyl                                                                       OH                                            2186                                                                               4-amidinophenyl                                                                           methyl                                                                              3-methylphenylcarbonyl                                                                      OMe                                           2187                                                                               4-amidinophenyl                                                                           methyl                                                                              3-methylphenylcarbonyl                                                                      OH                                            2188                                                                               4-amidinophenyl                                                                           methyl                                                                              3,5-dimethyl-                                                                               OMe                                                               isoxazoylcarbonyl                                          2189                                                                               4-amidinophenyl                                                                           methyl                                                                              3,5-dimethyl-                                                                               OH                                                                isoxazoylcarbonyl                                          2190                                                                               4-piperidinylethyl                                                                        methyl                                                                              phenylcarbonyl                                                                              OMe                                           2191                                                                               4-piperidinylethyl                                                                        methyl                                                                              phenylcarbonyl                                                                              OH                                            2192                                                                               4-piperidinylethyl                                                                        methyl                                                                              2,6-methylphenylcarbonyl                                                                    OMe                                           2193                                                                               4-piperidinylethyl                                                                        methyl                                                                              2,6-methylphenylcarbonyl                                                                    OH                                            2194                                                                               4-piperidinylethyl                                                                        methyl                                                                              2-methylphenylcarbonyl                                                                      OMe                                           2195                                                                               4-piperidinylethyl                                                                        methyl                                                                              2-methylphenylcarbonyl                                                                      OH                                            2196                                                                               4-piperidinylethyl                                                                        methyl                                                                              2-bromophenylcarbonyl                                                                       OMe                                           2197                                                                               4-piperidinylethyl                                                                        methyl                                                                              2-bromophenylcarbonyl                                                                       OH                                            2198                                                                               4-piperidinylethyl                                                                        methyl                                                                              3-methylphenylcarbonyl                                                                      OMe                                           2199                                                                               4-piperidinylethyl                                                                        methyl                                                                              3-methylphenylcarbonyl                                                                      OH                                            2200                                                                               4-piperidinylethyl                                                                        methyl                                                                              3,5-dimethyl-                                                                               OMe                                                               isoxazoylcarbonyl                                          2201                                                                               4-piperidinylethyl                                                                        methyl                                                                              3,5-dimethyl-                                                                               OH                                                                isoxazoylcarbonyl                                          2202                                                                               4-piperidinylethyl                                                                        methyl                                                                              n-butyloxycarbonyl                                                                          OH                                            __________________________________________________________________________

                                      TABLE 11                                     __________________________________________________________________________                                       (VI)                                          ##STR363##                                                                    Example                        MS                                              Number                                                                              R.sup.2                                                                              R.sup.8          Y  (M +  H).sup.+                                  __________________________________________________________________________     2220 H     CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                                                           OH                                                 2221 H     CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                                                           OH                                                 2222 H     CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                                                          OH                                                 2223 H     CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                                 OH                                                 2224 H     CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                                                        OH                                                 2225 H     CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                                                           OH                                                 2226 H     CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                                 OH                                                 2227 H                                                                                     ##STR364##      OH                                                 2228 H                                                                                     ##STR365##      OH                                                 2229 H                                                                                     ##STR366##      OH                                                 2230 H                                                                                     ##STR367##      OH                                                 2231 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                                                           OH                                                 2232 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                                                           OH                                                 2233 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                                                          OH                                                 2234 n-Bu  CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                                 OH                                                 2235 n-Bu  CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                                                        OH                                                 2236 n-Bu  CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                                                           OH                                                 2237 n-Bu  CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                                 OH                                                 2238 n-Bu                                                                                  ##STR368##      OH                                                 2239 n-Bu                                                                                  ##STR369##      OH                                                 2240 n-Bu                                                                                  ##STR370##      OH                                                 2241 n-Bu                                                                                  ##STR371##      OH                                                 2242 o-methoxy-                                                                           --CH.sub.2 CH.sub.3                                                                             OH                                                      benzyl                                                                    2243 o-methoxy-                                                                           --CH═CH.sub.2                                                                               OH                                                      benzyl                                                                    2244 o-methoxy-                                                                           --C.tbd.CH       OH                                                      benzyl                                                                    2245 o-methoxy-                                                                           CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                                                           OH                                                      benzyl                                                                    2246 o-methoxy-                                                                           CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                                                           OH                                                      benzyl                                                                    2247 o-methoxy-                                                                           CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                                                          OH                                                      benzyl                                                                    2248 methoxy-                                                                             CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                                 OH                                                      benzyl                                                                    2249 o-methoxy-                                                                           CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                                                        OH                                                      benzyl                                                                    2250 o-methoxy-                                                                           CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                                                           OH                                                      benzyl                                                                    2251 o-methoxy-                                                                           CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                                 OH                                                      benzyl                                                                    2252 o-methoxy-  benzyl                                                                    ##STR372##      OH                                                 2253 o-methoxy-  benzyl                                                                    ##STR373##      OH                                                 2254 o-methoxy-  benzyl                                                                    ##STR374##      OH                                                 2255 o-methoxy-  benzyl                                                                    ##STR375##      OH                                                 2256 o-methoxy-                                                                           --CH.sub.2 CH.sub.3                                                                             OH                                                      benzyl                                                                    2257 o-methoxy-                                                                           --CH═CH.sub.2                                                                               OH                                                      benzyl                                                                    2258 o-methoxy-                                                                           --C.tbd.CH       OH                                                      benzyl                                                                    __________________________________________________________________________

                  TABLE 12                                                         ______________________________________                                          ##STR376##                                                                    Ex.                                    MS                                      No.  R.sup.1   R.sup.16      m    n    (M +  H).sup.+                          ______________________________________                                         2280 guanidino benzyloxycarbonyl                                                                            2    2    449                                     2281 guanidino benzyloxycarbonyl                                                                            1    2    435                                     2282 guanidino benzyloxycarbonyl                                               2283 guanidino benzyloxycarbonyl                                               2284 guanidino benzyloxycarbonyl                                               2285 guanidino benzyloxycarbonyl                                               ______________________________________                                    

                  TABLE 13                                                         ______________________________________                                          ##STR377##                                                                    Ex.                                    MS                                      No.  R.sup.1   R.sup.16      m    n    (M +  H).sup.+                          ______________________________________                                         2400 guanidino benzyloxycarbonyl                                                                            2    2    449                                     2401 guanidino benzyloxycarbonyl                                                                            3    0    435                                     2402 guanidino benzyloxycarbonyl                                                                            5    0    463                                     2403 guanidino benzyloxycarbonyl                                                                            3    2    463                                     2404 guanidino benzyloxycarbonyl                                                                            4    2    477                                     2405 guanidino benzyloxycarbonyl                                                                            2    0    421                                     2406 guanidino benzyloxycarbonyl                                                                            4    0    449                                     ______________________________________                                    

                  TABLE 14                                                         ______________________________________                                          ##STR378##                                                                    Ex                                    MS                                       No.  R.sup.1 -V   R.sup.16       Y    (M + H).sup.+                            ______________________________________                                         2420 4-piperidinylpropyl                                                                         n-butyloxycarbonyl                                                                            OMe  441                                      2421 4-piperidinylpropyl                                                                         4-methylphenylsulfonyl                                                                        OMe  495                                      2422 4-piperidinylpropyl                                                                         4-methylphenylsulfonyl                                                                        OH   481                                      2423 4-piperidinylpropyl                                                                         n-butyloxycarbonyl                                                                            OH   427                                      ______________________________________                                    

Utility

The compounds of this invention possess antiplatelet efficacy, as evidenced by their activity in standard platelet aggregation assays or platelet fibrinogen binding assays, as described below. A compound is considered to be active in these assays if it has an IC₅₀ value of less than about 1 mM. Platelet aggregation and fibrinogen binding assays which may be used to demonstrate the antiplatelet activity of the compounds of the invention are described below.

Platelet Aggregation Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin-free for at least two weeks prior to blood collection. Blood was collected into 10 mL citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150×g at room temperature, and platelet-rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500×g at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a aggregometer (PAP-4 Platelet Aggregation Profiler), using PPP as the blank (100% transmittance). 200 μL of PRP was added to each micro test tube, and transmittance was set to 0%. 20 μL of various agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added to each tube, and the aggregation profiles were plotted (% transmittance versus time). The results are expressed as % inhibition of agonist-induced platelet aggregation. For the IC₅₀ evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

Ester prodrugs were preincubated (10⁻³ M F.C.) with 100 IU/mL Porcine liver esterase (Sigma Chemical Co., St. Louis, Mo., #E-3128) for 2 hours at 37° C. Aliquots are then diluted in 0.1 M Tris, pH 7.4, to the desired concentrations. Aliquots of 20 μl of the esterase pretreated prodrugs are added to 200 μl of human platelet rich plasma. Samples were placed in platelet profiler (aggregometer) for 8 minutes at 37° C., followed by the addition of 100 μM Adenosine Diphosphate, (Sigma Chemical Co., St. Louis, Mo., #A-6521), to induce platelet aggregation. Platelet aggregation was allowed to proceed for 5 minutes. Percent inhibition is calculated using percent aggregation in the presence of the test compound divided by percent aggregation of control, times 100. This value is subtracted from 100, yielding percent inhibition. Calculation of IC₅₀ is performed on a Texas Instruments TI59 with an IC₅₀ program.

Purified GPIIb/IIIa-Fibrinogen Binding ELISA

The following reagents are used in the GPIIb/IIIa-fibrinogen binding ELISA:

purified GPIIb/IIIa (148.8 μg/mL);

biotinylated fibrinogen (˜1 mg/mL or 3000 nM);

anti-biotin alkaline phosphatase conjugate (Sigma no. A7418);

flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590);

phosphatase substrate (Sigma 104) (40 mg capsules);

bovine serum albumin (BSA) (Sigma no. A3294);

Alkaline Phosphatase buffer-0.1 M glycine-HCl, 1 mM MgCl₂.6H₂ O, 1 mM ZnCl₂, pH 10.4;

Binding buffer-20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl₂.2H₂ O, 0.02% NaN₃, pH 7.0;

Buffer A-50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl₂.2H₂ O, 0.02% NaN₃, pH 7.4;

Buffer A+3.5% BSA (Blocking buffer);

Buffer A+0.1% BSA (Dilution buffer); 2N NaOH.

The following method steps are used in the GPIIb/IIIa-fibrinogen binding ELISA:

Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 μL/well) overnight at 4° C. (Leave first column uncoated for non-specific binding). Cover and freeze plates at -70° C. until used. Thaw plate 1 hour at room temperature or overnight at 4° C. Discard coating solution and wash once with 200 μL Binding buffer per well. Block plate 2 hours at room temperature on shaker with 200 μL Buffer A+3.5% BSA (Blocking buffer) per well. Discard Blocking buffer and wash once with 200 μL Buffer A+0.1% BSA (Dilution buffer) per well. Pipet 11 μL of test compound (10× the concentration to be tested in Dilution buffer) into duplicate wells. Pipet 11 μL Dilution buffer into non-specific and total binding wells. Add 100 μL Biotinylated fibrinogen (1/133 in Dilution buffer, final concentration=20 nM) to each well. Incubate plates for 3 hours at room temperature on a plate shaker. Discard assay solution and wash twice with 300 μL Binding buffer per well. Add 100 μL Anti-biotin alkaline phosphatase conjugate (1/1500 in Dilution buffer) to each well. Incubate plates for 1 hour at room temperature on plate shaker. Discard conjugate and wash twice with 300 51 Binding buffer per well. Add 100 μL Phosphatase substrate (1.5 mg/mL in Alkaline phosphatase buffer) to each well. Incubate plate at room temperature on shaker until color develops. Stop color development by adding 25 μL 2N NaOH per well. Read plate at 405 nm. Blank against non-specific binding (NSB) well. % Inhibition is calculated as

    100-(Test Compound Abs/Total Abs)×100.

Platelet-Fibrinogen Binding Assay: Binding of ¹²⁵ I-fibrinogen to platelets was performed as described by Bennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, with some modifications as described below. Human PRP (h-PRP) was applied to a Sepharose column for the purification of platelet fractions. Aliquots of platelets (5×10⁸ cells) along with 1 mM calcium chloride were added to removable 96 well plates prior to the activation of the human gel purified platelets (h-GPP). Activation of the human gel purified platelets was achieved using ADP, collagen, arachidonate, epinephrine, and/or thrombin in the presence of the ligand, ¹²⁵ I-fibrinogen. The ¹²⁵ I-fibrinogen bound to the activated platelets was separated from the free form by centrifugation and then counted on a gamma counter. For an IC₅₀ evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

The compounds of Formula I of the present invention may also possess thrombolytic efficacy, that is, they are capable of lysing (breaking up) already formed platelet-rich fibrin blood clots, and thus are useful in treating a thrombus formation, as evidenced by their activity in the tests described below. Preferred compounds of the present invention for use in thrombolysis include those compounds having an IC₅₀ value (that is, the molar concentration of the compound capable of achieving 50% clot lysis) of less than about 1 μM, more preferably an IC₅₀ value of less than about 0.1 μM.

Thrombolytic Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin free for at least two weeks prior to blood collection, and placed into 10 ml citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 1500×g at room temperature, and platelet rich plasma (PRP) was removed. To the PRP was then added 1×10⁻³ M of the agonist ADP, epinephrine, collagen, arachidonate, serotonin or thrombin, or a mixture thereof, and the PRP incubated for 30 minutes. The PRP was centrifuged for 12 minutes at 2500×g at room temperature. The supernatant was then poured off, and the platelets remaining in the test tube were resuspended in platelet poor plasma (PPP), which served as a plasminogen source. The suspension was then assayed on a Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.), to determine the platelet count at the zero time point. After obtaining the zero time point, test compounds were added at various concentrations. Test samples were taken at various time points and the platelets were counted using the Coulter Counter. To determine the percent of lysis, the platelet count at a time point subsequent to the addition of the test compound was subtracted from the platelet count at the zero time point, and the resulting number divided by the platelet count at the zero time point. Multiplying this result by 100 yielded the percentage of clot lysis achieved by the test compound. For the IC₅₀ evaluation, the test compounds were added at various concentrations, and the percentage of lysis caused by the test compounds was calculated.

The compounds of Formula I of the present invention are also useful for administration in combination with anti-coagulant agents such as warfarin or heparin, or antiplatelet agents such as aspirin, piroxicam or ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or argatroban, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.

The compounds of Formula I of the present invention may also be useful as antagonists of other integrins such as for example, the α_(v) /β₃ or vitronectin receptor, α₄ /β₁ or α₅ /β₁ and as such may also have utility in the treatment and diagnosis of osteoporosis, cancer metastasis, diabetic retinopathy, rheumatoid arthritis, inflammation, and autoimmune disorders. The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.

Table A below sets forth the antiplatelet activity of representative compounds of the present invention. The indicated compounds were tested for their ability to inhibit platelet aggregation (using platelet rich plasma (PRP)). The IC₅₀ value (the concentration of antagonist which inhibits platelet aggregation by 50% relative to a control lacking the antagonist) is shown. In Table 5 the IC₅₀ values are expressed as: +++=IC₅₀ of <10 μM; ++=IC₅₀ of 10-50 μM; +=IC₅₀ of 50-100 μM (μM=micromolar).

                  TABLE A                                                          ______________________________________                                                       Platelet     Platelet                                                          Aggregation Assay                                                                           Aggregation Assay                                                 IC.sub.50 (without                                                                          IC.sub.50 (with                                     Example Number                                                                               esterase)    esterage)                                           ______________________________________                                           1           +++                                                                4 (isomer A)                                                                               ++                                                                 4 (isomer B)                                                                               ++                                                                 7           >100                                                               8           +                                                                  9 (isomer A)                                                                               +++                                                                9 (isomer B)                                                                               +++                                                               33           >100                                                              43           +++                                                               89                        +++                                                  115                       +++                                                  119A (3R)                 +++                                                  119B (3S)                 +++                                                  120A (3R)                 +++                                                  120B (3S)                 +++                                                  120C (3R)†† +++                                                  166                       +++                                                  189          >100                                                              190          +                                                                 275                       +++                                                  276                       +++                                                  278                       +++                                                  290                       +++                                                  300                       +++                                                  312                       +++                                                  314A (2S)†         +++                                                  314B (2S)†† +++                                                  323                       +++                                                  324                       +++                                                  326                       +++                                                  327 (2S)                  +++                                                  328 (2S)                  +++                                                  338 (3S)     +            +++                                                  339 (3S)     +++                                                               340 (3S)     +            ++                                                   341 (3S)     +++                                                               342 (2S)     +++                                                               344 (3R)                  +++                                                  345                       +++                                                  347 (3R)††  +++                                                  348 (3R)                  +++                                                  350                       +++                                                  359                       +++                                                  362                       +++                                                  365                       +++                                                  368                       +++                                                  373          ++                                                                371A                      +++                                                  371B                      +++                                                  374 (2S)     +            +++                                                  375*         +++                                                               377          +++                                                               394                       +++                                                  394Aft                    +++                                                  400          +++                                                               413*                      +++                                                  415                       +++                                                  435                       +++                                                  436                       +++                                                  437                       +++                                                  438                       +++                                                  439                       +++                                                  440                       +++                                                  441          +++                                                               442                       +++                                                  443 (2S)                  +++                                                  444 (2S)                  +++                                                  445 (2S)                  +++                                                  446                       +++                                                  449A                      +++                                                  449B                      +++                                                  450                       +++                                                  451                       +++                                                  452                       +++                                                  453                       +++                                                  454                       +++                                                  455                       +++                                                  456                       +++                                                  457                       +++                                                  458A         +++                                                               458B         +++                                                               460A         +++                                                               460B         +++                                                               462                       +++                                                  463          +++                                                               464                       +++                                                  465                       +++                                                  466                       +++                                                  467                       +++                                                  468                       +++                                                  469                       +++                                                  470                       +++                                                  471                       +++                                                  472                       +++                                                  473A (2S)†         +++                                                  473B (2S)†† +++                                                  474                       +++                                                  475                       +++                                                  476                       +++                                                  477                       +++                                                  478                       +++                                                  479                       +++                                                  480                       +++                                                  481                       +++                                                  482                       +++                                                  483                       +++                                                  484                       +++                                                  485                       +++                                                  486                       +++                                                  487                       +++                                                  488                       +++                                                  489                       +++                                                  490                       +++                                                  491                       +++                                                  492                       +++                                                  493                       +++                                                  494                       +++                                                  495                       +++                                                  596                       +++                                                  504                       +++                                                  505                       +++                                                  506                       +++                                                  507                       +++                                                  508                       +++                                                  509                       +++                                                  510                       +++                                                  511                       +++                                                  512                       +++                                                  513                       +++                                                  514                       +++                                                  515                       +++                                                  516                       +++                                                  517                       +++                                                  518                       +++                                                  519                       +++                                                  520                       +++                                                  522                       +++                                                  523                       +++                                                  524                       +++                                                  525                       +++                                                  526          +++                                                               527                       +++                                                  528          +++                                                               529                       +++                                                  530          +++                                                               531                       +++                                                  532          +++                                                               533                       +++                                                  534          +++                                                               535                       +++                                                  536          +++                                                               537                       +++                                                  538          +++                                                               539                       +++                                                  540                       +++                                                  541                       +++                                                  542                       +++                                                  543                       +++                                                  544                       +++                                                  545                       +++                                                  546                       +++                                                  547                       +++                                                  548                       +++                                                  549                       +++                                                  550                       +++                                                  551                       +++                                                  552                       +++                                                  553                       +++                                                  554                       +++                                                  555                       +++                                                  556                       +++                                                  587A (2S)††                                                                   +++                                                               588                       +++                                                  602                       +++                                                  611                       +++                                                  612                       +++                                                  613                       +++                                                  616          +++                                                               642                       +++                                                  643                       +++                                                  644                       +++                                                  651                       +++                                                  727                       +++                                                  729                       +++                                                  798                       +++                                                  829                       +++                                                 1284                       +++                                                 1321                       +++                                                 1525                       +++                                                 1694                       +++                                                 1731                       +++                                                 2104                       +++                                                 2109                       +++                                                 2110                       +++                                                 2111                       +++                                                 2112                       +++                                                 2113                       +++                                                 2114                       +++                                                 2115                       +++                                                 2116                       +++                                                 2117                       +++                                                 2118                       +++                                                 2119                       +++                                                 2120                       +++                                                 2280                       +++                                                 2281                       +++                                                 2400                       +++                                                 2401                       +++                                                 2402                       +++                                                 2403                       +++                                                 2404                       +++                                                 2405                       +++                                                 2406                       +++                                                 ______________________________________                                          * Single diastereomer, racemic                                                 f S isomer at C5 of isoxazoline ring                                           ††R isomer at C5 of isoxazoline ring                       

The compounds of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thrombosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other angiogenic disorders.

The compounds of the formulae (Ie) and (If) possess selectivity as antagonists of integrins such as the α_(v) /β₃ vitronectin receptor. ##STR379##

The integrin antagonist activity of the compounds of the present invention is demonstrated using assays which measure the binding of a specific integrin to a native ligand, for example, using the ELISA assay described below for the binding of vitronectin to the α_(v) /β₃ receptor. The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit integrin-ligand binding. These would be provided in commercial kits comprising a compound of this invention.

Purified α_(v) /β₃ (human placenta)--Vitronectin ELISA:

The α_(v) /β₃ receptor was isolated from human placental extracts prepared using octylglucoside. The extracts were passed over an affinity column composed of anti-α_(v) /β₃ monoclonal antibody (LM609) to Affigel. The column was subsequently washed extensively at pH 7 and pH 4.5 followed by elution at pH 3. The resulting sample was concentrated by wheat germ agglutinin chromatography to provide gave two bands on SDS gel which were confirmed as α_(v) /β₃ by western blotting.

Affinity purified protein was diluted at different levels and plated to 96 well plates. ELISA was performed using fixed concentration of biotinylated vitronectin (approximately 80 nM/well). This receptor preparation contains the α_(v) /β₃ with no detectable levels of α_(v) /β₅ according to the gel (α_(v) /β₃) and according to effects of blocking antibodies for the α_(v) /β₃ or α_(v) /β₅ in the ELISA.

A submaximal concentration of biotinylated vitronectin was selected based on conc. response curve with fixed receptor conc. and variable concentrations of biotinylated vitronectin.

α_(v) /β₃ -Vitronectin Binding Assay

The purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl₂, 1.0 mM MgCl₂.6H₂ O, 1.0 mM MnCl₂.4H₂ O) and coated (100 μl/well) on Costar (3590) high capacity binding plates overnight at 4° C. The coating solution is discarded and the plates washed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCl, 100 mM NaCl, 2.0 mM CaCl₂, 1.0 mM MgCl₂.6H₂ O,1.0 mM MnCl₂.4H₂ O). Receptor is then blocked (200 μl/well) with 3.5% BSA in B/B buffer for 2 hours at room temperature. After washing once with 1.0% BSA in B/B buffer, biotinylated vitronectin (100 μl) and either inhibitor (11 μl) or B/B buffer w/1.0% BSA (11 μl) is added to each well. The plates are incubated 2 hours at room temperature. The plates are washed twice with B/B buffer and incubated 1 hour at room temperature with anti-biotin alkaline phosphatase (100 μl/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 μl) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 μl/well) and absorbance is read at 405 nm. The IC₅₀ is the concentration of test substance needed to block 50% of the vitronectin binding to the receptor.

Integrin Cell-Based Adhesion Assays

In the adhesion assays, a 96 well plate was coated with the ligand (i.e., fibrinogen) and incubated overnight at 4° C. The following day, the cells were harvested, washed and loaded with a fluorescent dye. Compounds and cells were added together and then were immediately added to the coated plate. After incubation, loose cells are removed from the plate, and the plate (with adherent cells) is counted on a fluorometer. The ability of test compounds to inhibit cell adhesion by 50% is given by the IC₅₀ value and represents a measure of potency of inhibition of integrin mediated binding. Compounds were tested for their ability to block cell adhesion using assays specific for α_(v) /β₃, α_(v) /β₅ and α₅ /β₁ integrin interactions.

Dosage and Formulation

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. Finally, the compounds of the invention may also be administered intranasally.

The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents, such as a second antiplatelet agent such as aspirin or ticlopidine which are agonist-specific. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

We have unexpectedly found that delivery of Example 327 (and it's free acid Example 300) through the nasal route provided very high bioactivity (inhibition of platelet aggregation) that was similar to that observed after administering the same dose intravenously. Also dog to dog variability was very small. For example, nasal and i.v. administration of 0.025 mg/kg gave similar profiles of platelet aggregation inhibition, however comparable effect after oral administration was only seen at doses equal or greater than 0.4 mg/kg. Therefore, the advantages of delivering Example 327 nasally are to enhance bioavailability and reduce variability. The latter is very important due to the steep dose response of these types of compounds.

The active ingredient can be administered intranasally to a mammal at a dosage range of about 0.01 to 0.5 mg/kg while the preferred dosage range is about 0.01-0.1 mg/kg.

Compositions of the active ingredients can be administered intranasally by preparing a suitable formulation of the active ingredient by procedures well known to those skilled in the art. Preferably the formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON'S PHARMACEUTICAL SCIENCES. 17th edition, 1985 a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, jelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

An example of a nasal solution composition of this invention includes:

    ______________________________________                                         Active Drug           0.2-2 g                                                  Sorbitol              0.6 g                                                    Benzalkonium chloride 0.002 g                                                  Hydrochloric acid     to adjust pH                                             Sodium hydroxide      to adjust pH                                             Purified water        to 10 mL                                                 ______________________________________                                    

In this example the active drug can be in one vial and the rest of the formulation can be in another vial. The drug can be reconstituted when needed.

The formulation of this invention may be varied to include: (1) other acids and bases to adjust the pH; (2) other tonicity imparting agents such as glycerin and dextrose; (3) other antimicrobial preservatives such as other parahydroxy benzoic acid esters, sorbate, benzoate, propionate, chlorbutanol, phenylethyl alcohol, and mercurials; (4) other viscosity imparting agents such as sodium carboxy-methylcellulose microcrystalline cellulose, polyvinyl-pyrrolidone, polyvinyl alcohol and other gums; (5) suitable absorption enhancers; (6) stabilizing agents such as antioxidants, like bisulfite and ascorbate, metal chelating agents such as sodium edetate and drug solubility enhancers such as polyethylene glycols.

The above formulation can be administered as drops, sprays, aerosols or by any other intranasal dosage form. Optionally, the delivery system can be a unit dose delivery system. The volume of solution or suspension delivered per dose can be anywhere from 5 to 400 μL, and preferably between 50 and 150 μL. Delivery systems for these various dosage forms can be dropper bottles, plastic squeeze units, atomizers, nebulizers or pharmaceutical aerosols in either unit dose or multiple dose packages.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1-20 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 1-20 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 1-20 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 mL contain 1-20 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered in combination with a second therapeutic agent selected from: an anti-coagulant agent such as warfarin or heparin; an anti-platelet agent such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as a boropeptide thrombin inhibitor, or hirudin; or a thrombolytic agent such as plasminogen activators, such as tissue plasminogen activator, anistreplase, urokinase or streptokinase. The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.

The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent). When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic agent occurs less than about one hour apart.

A preferable route of administration of the compound of Formula I is oral. Although it is preferable that the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

Although the proper dosage of the compound of Formula I when administered in combination with the second therapeutic agent will be readily ascertainable by a medical practitioner skilled in the art, once armed with the present disclosure, by way of general guidance, where the compounds of this invention are combined with anti-coagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the anti-coagulant, per kilogram of patient body weight. For a tablet dosage form, the novel compounds of this invention generally may be present in an amount of about 1 to 10 milligrams per dosage unit, and the anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with a second anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the additional anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Further, by way of general guidance, where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced) For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, for example, in the inhibition of platelet aggregation, the treatment of blood clots, and/or the treatment of thromboembolic disorders, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized. 

What is claimed is:
 1. A compound of Formula I: ##STR380## or pharmaceutically acceptable salt form thereof wherein: b is a carbon-carbon single or double bond;R¹ is selected from R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)(CH₂)_(q) Z--, piperazinyl--(CH₂)_(q) Z-- or ##STR381## Z is selected from O, S, S(═O), or S(═O)₂ ; R² and R³ are independently selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₆ -C₁₀ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl, aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; U is selected from:a single bond, --(C₁ -C₇ alkyl)--, --(C₂ -C₇ alkenyl)--, --(C₂ -C₇ alkynyl)--, --(aryl)--substituted with 0-3 R^(6a), or --(pyridyl)--substituted with 0-3 R^(6a) ; V is selected from:a single bond; --(C₁ -C₇ alkyl)--, substituted with 0-3 groups independently selected from R⁶ or R⁷ ; --(C₂ -C₇ alkenyl)--, substituted with 0-3 groups independently selected from R⁶ or R⁷ ; --(C₂ -C₇ alkynyl)--, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; -(aryl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; -(pyridyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or -(pyridazinyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; W is selected from:a single bond, --(C₁ -C₇ alkyl)-, --(C₂ -C₇ alkenyl)-, --(C₂ -C₇ alkynyl)-, or --(C(R⁵)₂)_(n) C(═O) N(R^(5a))--; X is selected from:a single bond; --(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁴, R⁸ or R¹⁴ ; --(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁴, R⁸ or R¹⁴ ; --(C₂ -C₇ alkynyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; or ##STR382## Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; or (R²)(R³)N--(C₁ -C₁₀ alkoxy)-; R⁴ and R^(4b) are independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ; R⁵ is selected from H, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁ arylalkyl, adamantylmethyl or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; alternately, R⁵ and R⁵ a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁ arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl; R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O) NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R^(5a), SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl; C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; methylenedioxy when R⁶ is a substituent on aryl; or a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ; R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ; R⁷ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O)NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R^(5a), SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, or C₇ to C₁₁ arylalkyl; R⁸ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ; C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶ ; C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ; C₅ -C₆ cycloalkenyl, substituted with 0-2 R⁶ ; aryl, substituted with 0-2 R⁶ ; - 10membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ; R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl(C₁ -C₁₀ alkoxy)carbonyl; R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ; R¹⁵ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ; C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ; aryl, substituted with 0-5 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ; C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ; CO₂ R⁵ ; or --C(═O)N(R⁵)R^(5a) ;provided that when b is a double bond, only one of R¹⁴ or R¹⁵ is present; n is 0-4; q is 2-7; r is 0-3;provided that n, q, and r are chosen such that the number of atoms connecting R¹ and Y is in the range of 8-18.
 2. A compound of claim 1 of Formula II: ##STR383## wherein: R¹ is selected from R² HN(CH₂)_(q) O--, R² HN(R² N)CNH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, or ##STR384## R² is selected from H, aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₁₀ alkoxycarbonyl;R⁸ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; R⁶ and R⁷ are selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo.
 3. A compound of claim 2 wherein:X is selected from:a single bond; --(C₁ -C₇ alkyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; --(C₂ -C₇ alkenyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; --(C₂ -C₇ alkynyl)-, substituted with 0-2 groups independently selected from R⁴, R⁸ or R¹⁴ ; R⁸ is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated.
 4. A compound of claim 2 wherein:R¹ is ##STR385## V is phenylene or pyridylene; n is 1 or 2; X is --(C₁ -C₂)alkyl-substituted with 0-2 R⁴ Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-;1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R⁴ is --NR¹² R¹³ ; R¹² is H, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄ alkylsulfonyl, arylalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl; R¹³ is H.
 5. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, selected from:5(R,S) -3-[[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid; 5(R,S)-N-(butanesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine; 5(R,S)-N-(α-toluenesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine; 5(R,S) -N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine; 5(R,S)-N-(pentanoyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine; 5(R,S)-3-{[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)-N-(butanesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)-N-(α-toluenesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)-N-[(benzyloxy)carbonyl]amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)-N-(pentanoyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid.
 6. A compound of Formula Id: ##STR386## or a pharmaceutically acceptable salt form thereof wherein: R¹ is selected from is selected from R² (R³)N--, R² (R³)N(R² N═)C--, R² (R³)N(R² N═)CN(R²)--, R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)(CH₂)_(q) Z--, piperazinyl-(CH₂)_(q) Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--, ##STR387## Z is selected from a bond, O, S, S(═O), or S(═O)₂ ; R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;provided that only one of R² and R³ may be hydroxy; U is selected from:a single bond, C₁ -C₇ alkylene, C₂ -C₇ alkenylene, C₂ -C₇ alkynylene, arylene substituted with 0-3 R^(6a), or pyridylene substituted with 0-3 R^(6a) ; V is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ; C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ; C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ; phenylene substituted with 0-4 R⁶ or R⁷ ; pyridylene substituted with 0-3 R⁶ or R⁷ ; pyridazinylene substituted with 0-3 R⁶ or R⁷ ; X is selected from:a single bond; --(CH₂)_(n) C(═O)N(R¹²)--; C₁ -C₇ alkylene substituted with 0-6 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkenylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkynylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ; Y is selected from:hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R²) (R³)N--(C₁ -C₁₀ alkoxy)-; R¹⁴ and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR388## D, E, F and G are each independently selected from: C(R^(6a))₂ ;carbonyl; a heteroatom moiety selected from N, N(R¹²), O, provided that no more than 2 of D, E, F and G are N, N(R¹²), O, S, or C(═O); alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon-carbon double bond; R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ; R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R^(5a), C(═O)R^(5a), CONHR^(5a), CON(R¹²)₂, OC(═O)R^(5a), OC(═O)OR^(5a), OR^(5a), OC(═O)N(R¹²)₂, OCH₂ CO₂ R^(5a), CO₂ CH₂ CO₂ R^(5a), N(R¹²)₂, NO₂, NR¹² C(═O) R^(5a), NR¹² C(═O)OR^(5a), NR¹² C(═O)N(R¹²)₂, NR¹² SO₂ N(R¹²)₂, NR¹² SO₂ R^(5a), S(O)_(p) R^(5a), SO₂ N(R¹²)₂, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; methylenedioxy when R⁶ is a substituent on aryl; R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ; R⁸ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ; C₂ -C₁₀ alkynyl, substituted with 0-6 R⁶ ; C₃ -C₈ cycloalkyl, substituted with 0-6 R⁶ ; C₅ -C₆ cycloalkenyl, substituted with 0-5 R⁶ ; aryl, substituted with 0-5 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ; R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryl groups and heteroaryl groups are optionally substituted with 0-3 substituents selected from: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; R⁵ and R^(5a) are selected independently from H, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-8 R⁴ ; R¹⁵ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ; C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ; aryl, substituted with 0-5 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ; C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ; CO₂ R⁵ ; or --C(═O)N(R¹²)R¹³ ; n is 0-4; p is 1-3; q is 1-7; r is 0-3;provided that n, p, q and r are chosen such that the number of atoms connecting R¹ and Y is in the range of 8-17.
 7. A compound of claim 6 of Formula III: ##STR389## wherein: R¹ is selected from R² HN--, H₂ N(R² N═)C--, H₂ N(R² N═)CNH--, R² HN(CH₂)_(q) O--, H₂ N(R² N═)CNH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--, ##STR390## R² and R³ are selected from H; C₁ -C₆ alkyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C₁ -C₅)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or C₁ -C₁₀ alkoxycarbonyl;R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ; V is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ; C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ; C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ; phenylene substituted with 0-3 R⁶ or R⁷ ; pyridylene substituted with 0-3 R⁶ or R⁷ ; pyridazinylene substituted with 0-3 R⁶ or R⁷ ; X is selected from --(CH₂)_(n) C(═O)N(R¹²)--, C₁ -C₇ alkylene substituted with 0-1 R⁴, C₂ -C₇ alkenylene, or C₂ -C₇ alkynylene; Y is selected from:hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; Z is selected from 0 or CH₂ ; D, E, F and G are each independently selected from:CH₂ ; carbonyl; a heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S; alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon-carbon double bond; R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R₁₃, cyano, or halo; R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; n is 0-4; p is 1-3; q is 1-7; r is 0-3;provided that n, p, q and r are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.
 8. A compound of claim 7 wherein:R¹ is R² NHC(═NR²)-- and V is phenyl or pyridyl or R¹ is ##STR391## and V is a single bond; n is 1 or 2; X is C₁ -C₄ alkylene substituted with 0-1 R⁴ ; Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R¹² and R¹³ are each independently selected from H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and R¹³ is H.
 9. A compound of claim 6, or pharmaceutically acceptable salt forms thereof, selected from:5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one; 5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one; 5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione; 5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione; 5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one; 5(R,S) -3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione; 5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5,7-dione; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one; 5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one; 5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one; 5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one; 5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-[2-(benzyloxycarbonylamino)-2-carboxyethyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene.
 10. A compound of Formula I: ##STR392## or pharmaceutically acceptable salt form thereof, wherein: b is a carbon-carbon single bond or double bond;R¹ is selected from:R² (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)N(R² N═)CN(R²)(CH₂)_(q) Z--, piperazinyl-(CH₂)_(q) Z-- or ##STR393## Z is selected from O, S, S(═O), S(═O)₂ ; R² and R³ are independently selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₀ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl, C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; U is optionally present and is selected from C₁ -C₇ alkylene, C₂ -C₇ alkenylene, C₂ -C₇ alkynylene, arylene, or pyridylene; V is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ; C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ; C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ; phenylene substituted with 0-4 R⁶ or R⁷ ; pyridylene substituted with 0-3 R⁶ or R⁷ ; pyridazinylene substituted with 0-3 R⁶ or R⁷ ; W is -(aryl)-Z¹ --, wherein said aryl is substituted with 0-6 R⁶ or R⁷ ; Z¹ is selected from a single bond, --CH₂ --, O or S; X is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-6 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkenylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkynylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ; Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R²)(R³)N--(C₁ -C₁₀ alkoxy)-; R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ; R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R^(5a), C(═O)R^(5a), CONHR^(5a), CON(R¹²)₂, OC(═O)R^(5a), OC(═O)OR^(5a), OR^(5a), OC(═O)N(R¹²)₂, OCH₂ CO₂ R^(5a), CO₂ CH₂ CO₂ R^(5a), N(R¹²)₂, NO₂, NR¹² C(═O)R^(5a), NR¹² C(═O)OR^(5a), NR¹² C(═O)N(R¹²)₂, NR¹² SO₂ N(R¹²)₂, NR¹² SO₂ R^(5a), S(O)_(p) R^(5a), SO₂ N(R¹²)₂, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;C₆ to C₁₀ aryl optionally substituted with halogen, alkoxy, alkyl, --CF₃, S(O)_(m) Me, or --NMe₂ ; or C₇ to C₁₁ arylalkyl said aryl being optionally substituted with halogen, alkoxy, alkyl, --CF₃, S(O)_(m) Me, or --NMe₂ ; R⁸ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ; C₂ -C₁₀ alkynyl, substituted with 0-6 R⁶ ; C₃ -C₈ cycloalkyl, substituted with 0-6 R⁶ ; C₅ -C₆ cycloalkenyl, substituted with 0-5 R⁶ ; aryl, substituted with 0-5 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ; R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl, C₇ -C₁₁ arylcarbonyl, C₂ -C₁₀ alkoxycarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl (C₁ -C₁₀ alkoxy) carbonyl; R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R¹²)R¹³ ; R⁵ and R^(5a) are selected independently from H, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-8 R⁴ ; R¹⁵ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-8 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-6 R⁶ ; C₁ -C₁₀ alkoxy, substituted with 0-6 R⁶ ; aryl, substituted with 0-5 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R⁶ ; C₁ -C₁₀ alkoxycarbonyl substituted with 0-8 R⁶ ; CO₂ R⁵ ; or --C(═O)N(R¹²)R¹³ ; n is 0-4; q is 2-7; r is 0-3;provided that n, q, and r are chosen such that the number of atoms between R¹ and Y is about 8-17.
 11. A compound of claim 10 of Formula IV: ##STR394## wherein: b is a carbon-carbon single bond or double bond;R¹ is selected from R² HN(CH₂)_(q) O--, R² HN(R² N═C)NH(CH₂)_(q) O--, piperazinyl-(CH₂)_(q) O--, or ##STR395## Z is O; R² is selected from H, aryl(C₁ -C₁₀)alkoxycarbonyl, C₁ -C₁₀ alkoxycarbonyl; V is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-6 R⁶ or R⁷ ; C₂ -C₇ alkenylene substituted with 0-4 R⁶ or R⁷ ; C₂ -C₇ alkynylene substituted with 0-4 R⁶ or R⁷ ; phenylene substituted with 0-3 R⁶ or R⁷ ; pyridylene substituted with 0-3 R⁶ or R⁷ ; pyridazinylene substituted with 0-3 R⁶ or R⁷ ; Z¹ is selected from a single bond, O or S; X is selected from:a single bond; C₁ -C₇ alkylene substituted with 0-4 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkenylene substituted with 0-3 R⁴, R⁸ or R¹⁵ ; C₂ -C₇ alkynylene substituted with 0-3 R⁴, R⁸ or R¹⁵ ; Y selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; R⁴ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, or --N(R¹²)R¹³ ; R⁶ and R⁷ are selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo; R⁸ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₆ cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; R¹² and R¹³ are independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl; R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R¹²)R¹³ ; R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R⁴ ; n is 0-4; q is 2-7;provided that n and q are chosen such that the number of atoms between R¹ and Y is in the range of 8-17.
 12. A compound of claim 1, wherein:R¹ is R² HN(CH₂)_(q) O-- or ##STR396## V is C₁ -C₃ alkylene; Z¹ is a single bond or O; X is C₁ -C₃ alkylene substituted with 0-1 R⁴ ; Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R¹² and R¹³ are independently selected from H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyl, C₁ -C₆ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl; R¹³ is H.
 13. A compound of claim 10, or a pharmaceutically acceptable salt form thereof, selected from:5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]hydrocinnamic acid; 5(R,S)-4-[3-(2-aminoethoxymethyl),isoxazolin-5-yl]hydrocinnamic acid; 5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]hydrocinnamic acid; 5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]phenoxyacetic acid; 5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]phenoxyacetic acid; 5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]phenoxyacetic acid.
 14. A compound of Formula I: ##STR397## or a pharmaceutically acceptable salt form thereof wherein: b is a carbon-carbon single or double bond;R¹ is selected from R^(2a) (R³)N--, R² (R³)N(R² N═)C--, R^(2a) (R³)N(CH₂)_(q) Z--, R² (R³)N(R² N═)C(CH₂)_(q) Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--; ##STR398## Z is selected from a bond, O, S, S(═O), S(═O)₂ ; R² and R³ are independently selected from: H; C₁ -C₁₀ alkyl; C₃ -C₆ alkenyl; C₃ -C₁₁ cycloalkyl; C₄ -C₁₁ cycloalkylalkyl; C₆ -C₁₀ aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₂ -C₇ alkylcarbonyl; C₇ -C₁₁ arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; C₄ -C₁₁ cycloalkoxycarbonyl; C₇ -C₁₁ bicycloalkoxycarbonyl; C₇ -C₁₁ aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₆ alkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; C₆ -C₁₀ arylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₄ -C₁₁ cycloalkylcarbonyloxy(C₁ -C₄ alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;provided that only one of R² and R³ may be hydroxy; R^(2a) is R² or R² (R³)N(R² N═)C; U is selected from:a single bond, --(C₁ -C₇ alkyl)-, --(C₂ -C₇ alkenyl)-, --(C₂ -C₇ alkynyl)-, -(aryl)- substituted with 0-3 R⁶ -, or -(pyridyl)- substituted with 0-3 R^(6a) ; V is selected from:a single bond; --(C₁ -C₇ alkyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ; --(C₂ -C₇ alkenyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ; --(C₂ -C₇ alkynyl)-, substituted with 0-3 groups independently selected from R⁶ or R⁷ ; -(phenyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; -(pyridyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; or -(pyridazinyl)-, substituted with 0-2 groups independently selected from R⁶ or R⁷ ; W is selected from: ##STR399## X is selected from: a single bond,--(C(R⁴)₂)_(n) --C(R⁴)(R⁸)--C(R⁴)(R^(4a))--, with the proviso that when n is 0 or 1, then at least one of R^(4a) or R⁸ is other than H or methyl; Y selected from:hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R²)(R³)N--(C₁ -C₁₀ alkoxy)-; Z¹ is --C--, --O--, or --NR²² --; Z² is --O--, or --NR²² --; R⁴ is selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkylcarbonyl, aryl, arylalkylene cycloalkyl, or cycloalkylalkylene; alternately, two R⁴ groups on adjacent carbon atoms may join to form a bond, thereby to form a carbon-carbon double or triple bond between such adjacent carbon atoms; R^(4a) is selected from H, hydroxy, C₁ -C₁₀ alkoxy, nitro, N(R⁵)R^(5a), --N(R¹²)R¹³, --N(R¹⁶)R¹⁷, C₁ -C₁₀ alkyl substituted with 0-3 R⁶, aryl substituted with 0-3 R⁶, or C₁ -C₁₀ alkylcarbonyl; R^(4b) is selected from H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, hydroxy, C₁ -C₆ alkoxy; C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³ ; halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, or pyridyl; R⁵ is selected from H, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; R^(5a) is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆ to C₁₀ aryl, heteroaryl, C₇ to C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; alternately, R⁵ and R^(5a) when both are substituents on the same nitrogen atom (as in --NR⁵ R^(5a)) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆ alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁ arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl; R^(5b) is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R^(4b) ; R⁶ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR⁵, OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C(═O) NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(p) R⁵, SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl;C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; C₇ to C₁₁ arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ; methylenedioxy when R⁶ is a substiuent on aryl; or a 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁷ ; R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ; R⁷ is selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, halo, CF₃, CHO, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), OC(═O)R^(5a), OC(═O)OR^(5b), OR^(5a), OC(═O)NR⁵ R^(5a), OCH₂ CO₂ R⁵, CO₂ CH₂ CO₂ R⁵, NO₂, NR^(5a) C(═O)R^(5a), NR^(5a) C(═O)OR^(5b), NR^(5a) C (═O) NR⁵ R^(5a), NR^(5a) SO₂ NR⁵ R^(5a), NR^(5a) SO₂ R⁵, S(O)_(m) R^(5a), SO₂ NR⁵ R^(5a), C₂ to C₆ alkenyl, C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₆ to C₁₀ aryl, or C₇ to C₁₁ arylalkyl; R⁸ is selected from:R⁶ ; C₂ -C₁₀ alkyl, substituted with 0-3 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ; C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶ ; C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶ ; C₅ -C₆ cycloalkenyl, substituted with 0-3 R⁶ ; aryl, substituted with 0-3 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ; R¹² and R¹³ are independently H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, aryl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₇ -C₁₁ arylalkyl, C₇ -C₁₁ arylcarbonyl, C₄ -C₁₁ cycloalkoxycarbonyl, C₇ -C₁₁ bicycloalkoxycarbonyl, C₇ -C₁₁ aryloxycarbonyl, or aryl(C₁ -C₁₀ alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; R¹⁴ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ; R¹⁵ is selected from:H; R⁶ ; C₁ -C₁₀ alkyl, substituted with 0-3 R⁶ ; C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶ ; C₁ -C₁₀ alkoxy, substituted with 0-3 R⁶ ; aryl, substituted with 0-3 R⁶ ; - 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R⁶ ; C₁ -C₁₀ alkoxycarbonyl substituted with 0-2 R⁶ ; --CO₂ R⁵ ; or --C(═O)N(R¹²)R¹³ ;provided that when b is a double bond, only one of R¹⁴ or R¹⁵ is present; R¹⁶ is selected from:--C(═O)--O--R^(18a), --C(═O)--R^(18b), --C(═O)N(R^(18b))₂, --C(═O)NHSO₂ R^(18a), --C(═O)NHC(═O)R^(18b), --C(═O)NHC(═O)OR^(18a), --C(═O)NHSO₂ NHR^(18b), --C(═S)--NH--R^(18b), --NH--C(═O)--O--R^(18a), --NH--C(═O)--R^(18b), --NH--C(═O)--NH--R^(18b), --SO₂ --O--R^(18a), --SO₂ --R^(18a), --SO₂ --N(18^(b))₂, --SO₂ --NHC(═O)O18^(b), --P(═S)(OR^(18a))₂, --P(═O)(OR^(18a))₂, --P(═S)(R^(18a))₂, ##STR400## or R¹⁷ is selected from: H, C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₅ cycloalkylalkyl, aryl, aryl(C₁ -C₁₀ alkyl)-; R^(18a) is selected from:C₁ -C₈ alkyl substituted with 0-2 R¹⁹, C₂ -C₈ alkenyl substituted with 0-2 R¹⁹, C₂ -C₈ alkynyl substituted with 0-2 R¹⁹, C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-4 R¹⁹, aryl(C₁ -C₆ alkyl)- substituted with 0-4 R¹⁹, a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹, C₁ -C₆ alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R¹⁹ ; R^(18b) is selected from R^(18a) or H; R¹⁹ is selected from H, halogen, CF₃, CN, NO₂, NR¹² R¹³, C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, aryl, aryl(C₁ -C₆ alkyl)-, C₁ -C₆ alkoxy, or C₁ -C₄ alkoxycarbonyl; R²⁰ and R²¹ are each independently selected from H, C₁ -C₁₀ alkyl, CO₂ R⁵, C(═O)R^(5a), CONR⁵ R^(5a), NR⁵ C(═O)R^(5a), NR¹² R¹³, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, or C₇ -C₁₁ arylalkyl; R²² is selected from C₁ -C₁₀ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₅ cycloalkylalkyl, aryl, aryl(C₁ -C₁₀ alkyl)-; C(═O)R^(5a), CO₂ R^(5b), --C(═O)N(R⁵)R^(5a), or a bond to X; m is 0-2; n is 0-2; p is 1-2; q is 1-7; r is 0-3;provided that n, q and r are chosen such that the number of atoms connecting R¹ and Y is in the range of 8-17.
 15. A compound of claim 14 of Formula Ic: ##STR401## wherein: Z is selected from a bond, O, or S;R² and R³ are independently selected from: H; C₁ -C₆ alkyl; C₇ -C₁₁ arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy; C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C₁ -C₁₀ alkoxycarbonyl; aryl(C₁ -C₁₀ alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C₁ -C₅)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; U is a single bond; X is --CHR^(4a) --; R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-6 R^(4b) ; R⁶ and R⁷ are each independently selected from H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl, --N(R¹²)R¹³, cyano, or halo; R¹² and R¹³ are each independently selected from H, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxycarbonyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ alkylsulfonyl, aryl(C₁ -C₁₀ alkyl)sulfonyl, arylsulfonyl, heteroarylsulfonyl, or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; R¹⁵ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R⁵ or --C(═O)N(R⁵)R^(5a) ; R¹⁶ is selected from:--C(═O)--O--R^(18a), --C(═O)--R^(18b), --S(═O)₂ --R^(18a) ; R¹⁷ is selected from: H or C₁ -C₄ alkyl; R^(18a) is selected from:C₁ -C₈ alkyl substituted with 0-2 R¹⁹, C₂ -C₈ alkenyl substituted with 0-2 R¹⁹, C₂ -C₈ alkynyl substituted with 0-2 R¹⁹, C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-2 R¹⁹, aryl(C₁ -C₆ alkyl)- substituted with 0-2 R¹⁹, a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹ ; C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹.
 16. A compound of claim 14 of Formula Ib: ##STR402## wherein: R¹ is selected from: R² (R³)N--, R² NH(R² N═)C--, R² R³ N(CH₂)_(p") Z--, R² NH(R² N═)CNH(CH₂)_(p') Z--, R² (R³)NC(O)--, R² (R⁵ O)N(R² N═)C--, R² (R³)N(R⁵ ON═)C--; ##STR403## n is 0-1; p' is 2-4;p" is 4-6; Z is selected from a bond or O; R³ is H or C₁ -C₅ alkyl; V is a single bond, or -(phenyl)-; X is selected from:--CH₂ --, --CHN(R¹⁶)R¹⁷ --, or --CHNR⁵ R^(5a) --; Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R^(18a) is selected from:C₁ -C₄ alkyl substituted with 0-2 R¹⁹, C₂ -C₄ alkenyl substituted with 0-2 R¹⁹, C₂ -C₄ alkynyl substituted with 0-2 R¹⁹, C₃ -C₄ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-2 R¹⁹, aryl(C₁ -C₄ alkyl)- substituted with 0-2 R¹⁹, a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹ ; C₁ -C₆ alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R¹⁹.
 17. A compound of claim 16 wherein:R¹ is R² NH(R² N═)C-- or R² NH(R² N═)CNH-- and V is phenyl or pyridyl; or R¹ is ##STR404## and V is a single bond; n is 1-2; R³ is H or C₁ -C₅ alkyl; X is selected from:--CH₂ --, --CHN(R¹⁶)R¹⁷ --, or --CHNR⁵ R^(5a) --; W is selected from: ##STR405## m is 1-3; Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R¹⁹ is H, halogen, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, cyclopropylmethyl, aryl, or benzyl;R²⁰ and R²¹ are both H; R²² is H, C₁ -C₄ alkyl or benzyl.
 18. A compound of claim 14, or a pharmaceutically acceptable salt form thereof, selected from:2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine; 2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azepine; 2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine; 3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperazine-2-one; 6-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine-2-one; 5-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine-2-one; 7-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azetidine-2-one; 2-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrazolidine; 3-(R,S)-carboxymethyl-4-(5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]morpholine.
 19. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 1. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.
 21. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 1. 22. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 16. 23. A method for the treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16 in combination with one or more additional therapeutic agents selected from: a thrombolytic agent, an anti-coagulant agent, or an anti-platelet agent.
 24. A method of treating rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, organ transplantation rejection, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory conditions and inflammatory bowel disease, comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 16. 25. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable excipient, and water.
 26. A method of administering a compound of claim 1, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 27. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable excipient, and water.
 28. A method of administering a compound of claim 1, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 29. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 6, a pharmaceutically acceptable excipient, and water.
 30. A method of administering a compound of claim 6, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 31. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 10, a pharmaceutically acceptable excipient, and water.
 32. A method of administering a compound of claim 10, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 33. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 14 a pharmaceutically acceptable excipient, and water.
 34. A method of administering a compound of claim 14, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 35. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 6. 36. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutical effective amount of a compound of claim
 10. 37. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 11. 38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 and a pharmaceutically acceptable carrier.
 39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 and a pharmaceutically acceptable carrier.
 40. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14 and a pharmaceutically acceptable carrier.
 41. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 6. 42. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 10. 43. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 14. 44. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 6, a pharmaceutically acceptable excipient, and water.
 45. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 10, a pharmaceutically acceptable excipient, and water.
 46. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 14, a pharmaceutically acceptable excipient, and water.
 47. A method of administering a compound of claim 6 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 48. A method of administering a compound of claim 10 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
 49. A method of administering a compound of claim 19 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound. 